biochemistry of hyperthyroidism and hypothyroidism* · rna-metabolism and the earlier changes in...

Postgrad. med. J. (May 1968) 44, 347-362.

Biochemistry of hyperthyroidism and hypothyroidism*FREDERIC L. HOCH

B.S., M.S., M.D.

Biophysics Research Division, Institute of Science and Technology,The University of Michigan, Ann Arbor, Michigan 48104

SummaryThe thyroid hormones act directly on mito-

chondria, and thereby control the transformationof the energy derived from oxidations into a formutilizable by the cell. Through their direct actionson mitochondria, the hormones also control in-directly the rate of protein synthesis and therebythe amount of oxidative apparatus in the cell. Arationale for the effects of thyroid hormone excessor deficiency is based upon studies of themechanism of thyroid hormone action. In hypo-thyroidism, slow fuel consumption leads to a lowoutput of utilizable energy. In hyperthyroidism,rapid fuel consumption leads to a high energyoutput, but as efficiency decreases, the utilizableenergy produced decreases. Many of the chemicaland physical features of these diseases can bereduced to changes in available energy.

IntroductionExcess or deficiency in the amount of thyroid

hormones in humans produces clinical andchemical manifestations that involve a numberof organ and metabolic systems. Variations ofthyroid hormone concentrations in vivo changeoxygen consumption, temperature regulation,growth and development, the response to otherhormones, nerve function, and the metabolism ofproteins, fats, carbohydrates, nucleic acids, vita-mins, and inorganic anions and cations. On theother hand, thyroxine and triiodothyronine arerelatively simple molecules, and their small sizeand limited number of reactive groups suggesteither that the variety of the effects they pro-duce are due to a few types of primary inter-actions at the molecular level, or that the hor-mones are changed in the body to analogueseach having a different and specific physiologic

*Abbreviations: L-T,, L-thyroxine; L-T,, L-triiodo-thyronine; Triac, triiodothyroacetic acid; ATP, ADP andAMP, adenosine tri-, di- and mono-phosphate; P1, inorganicphosphate; NADH and NADPH, reduced nicotinamide-adenine dinucleotide and dinucleotide phosphate; DNP,2,4-dinitrophenol; BMR, basal metabolic rate (0O con-sumption).

effect. The preponderance of evidence at presentsupports the first hypothesis. It seems feasibletherefore to attempt to reduce the complexpathologic pictures to subcellular phenomenaand their consequences.Recent advances in the understanding of where

and how the thyroid hormones act in the cellsupport a simplification of thyrotoxicosis andhypothyroidism, although our understanding isnot as yet so far advanced as to permit a final'explanation' of the diseases in molecular terms.A brief history of the evolution of studies onthe mechanism of thyroid hormone action servesto outline the present state of knowledge, theareas in which future advances may be made,and a basis for a rationale of hyperthyroidismand hypothyroidism.Actions and effects of thyroid hormonesEver since Magnus-Levy (1895) showed that

the thyroid gland controlled the rate of oxygenconsumption in mammals, attention has beenfixed on oxidative processes as a target of thehormone. Kendall (1929) showed the structure ofthyroxine and suggested the hormone might bea component or coenzyme of an oxidativeenzyme, undergoing a redox cycle between thephenol and semiquinone forms. No evidencehas as yet been found to support Kendall's hypo-thesis conclusively. In the years 1940-50 it be-came clear that 90% or more of the cell'soxygen was consumed via processes occurringin mitochondria, and experiments were donewith thyroid hormones in vivo and in vitro todetermine their effects on mitochondria.One should differentiate, in considering these

studies, between actions of the hormones andeffects of the hormones. Actions may be definedas those functional or structural changes thatare primary and depend upon the presence ofthe hormone at a site where it interacts with amolecule in the cellular apparatus. Because hor-mones are effective in small amounts we mayassume that their primary molecular interactionsare reversible, so that the hormones are not

copyright. on M

arch 6, 2020 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.44.511.347 on 1 M

ay 1968. Dow

nloaded from

http://pmj.bmj.com/

Frederic L. Hoch

used up. Effects may be defined as those func-tional, structural, or compositional changes thatare secondary and do not depend upon the pres-ence of the hormone; they should not bereversed if the hormone is removed after acting.The differentiation between actions and effectsmakes no judgement on their relative importancein the cell. The thyroid hormones are peculiarlysuitable for the resolution of primary actionsfrom secondary effects, because their iodinemoieties can be used experimentally as a tracerfor quantitative analysis. Methods for detectingother hormones not possessing this useful pro-perty are less specific or more tedious.As will be detailed below, the thyroid hor-

mones were shown to affect mitochondria as2,4-dinitrophenol did: both agents increasedmitochondrial respiration, and the energy lib-erated was transformed into heat rather thaninto the normal utilizable form, the high-energyphosphate bond. This toxic, catabolic, energy-wasting effect served as a rationale for thyro-toxicosis (Hoch, 1962a), but not for the anabolicenergy-conserving effects that the smaller dosesof thyroid hormones exerted in euthyroid orhypothyroid subjects (Hoch, 1962b). Nor washypothyroidism made more understandable bythe 'uncoupling' hypothesis. Accordingly, atten-tion was directed away from the mitochrondrionin the search for the mechanism.

In the early 1960s the groups of Tata and ofSokoloff showed that thyroid hormones affectedprotein synthesis. It had been demonstratedearlier by Dutoit (1952) that protein was syn-thesized abnormally slowly in the livers of hypo-thyroid rats. L-T3 given in vivo acceleratedthe synthesis of proteins by ribosomes afterabout 48 hr after injection; the doses necessarywere small and physiologic, smaller than thoseproducing uncoupling in mitochondria, and theeffect of the hormone was obviously anabolic(see Tata, 1967). Puromycin and actinomycin D,agents that block protein synthesis by acting onnucleic acids, blocked the calorigenic action ofthyroid hormones (Tata, 1963; Weiss & Sokoloff,1963). No changes were observed in mitochon-drial respiratory control after hormone injec-tion (Tata et al., 1963). Respiratory accelerationcould be demonstrated in mitochondria 70-90hr after hormone injections, but it was due toincreases in the number of depleted respira-tory assemblies in the mitochondria of hypo-thyroid rats (Tata et al., 1963; Roodyn, Freeman& Tata, 1965), and so represented the specificresults of earlier protein synthesis. Increases innuclear RNA-metabolism were shown early (3-16 hr) after hormone injection (Tata & Widnell,

1966), then increases in ribosomal RNA-contentand aggregation (about 40 hr) (Tata, 1967). How-ever, although all these phenomena showed animportant relationship between the thyroid hor-mones and the processes supplying informationto and controlling the rate of protein synthesis,they did not show the primary locus of hormoneaction. When L-T3 was added to isolated nuclei,RNA-metabolism was not stimulated (Widnell &Tata, 1963; Tata & Widnell, 1966; Sokoloff,Francis & Campbell, 1964). Tata's conclusionsare diagrammed in Fig. 1.

T- -/- Nucleus -:> Ribosome = Protein > Mitochondrionsynthesis

3-16 40 48 70-90Time(hr) /i vivo

FIG. 1. Sequence of events after injecting hypothyroidrats with thyroid hormone (T = L-T,), according toTata and co-workers.

The studies of Sokoloff (Sokoloff & Kaufman,1959, 1961; Sokoloff et al., 1963, 1964) haverecently drawn attention back to the mitochon-drion as a site of action of the hormone (Fig. 2).

o2ASH.2 t-RNA-AA

T Mitochondrion n=>x >ATP Ribosomez= Protein synthesisGTP

5minin vitro Time 2hr:

in vivo

FIG. 2. Sequence of events after injecting hypothyroidrats with thyroid hormone, or after addition of thyroidhormone to mitochondria (T - L-T,), according toSokoloff and co-workers.

Adding L-T3 to a homogenate in vitro stimu-lated ribosomal synthesis of proteins. The pro-cesses whereby t-RNA-amino-acyl complexesinteracted with the ribosomes were the locus ofthe stimulation. Mitochondria oxidizing a sub-strate were necessary, and they apparently pro-duced a substance that accelerated the ribosomaltranslation; adding ATP, GTP or glutathione didnot replace the effect of hormone-treated mito-chondria. What it is that mitochondria produceto control ribosomal protein synthesis is not yetclear; studies by Bronk (1963) have suggestedthat mitochondrial non-phosphorylated, high-energy intermediates may support protein syn-thesis.Our recent studies have shown that L-T4 in-

jected in vivo can act rapidly and directly on

348copyright.

on March 6, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.44.511.347 on 1 May 1968. D

ownloaded from

http://pmj.bmj.com/

Biochemistry of hyperthyroidism and hypothyroidismmitochondria (Hoch, 1968a). Bronk (1966) hasalso shown a very short latent period for L-T8.In hypothyroid rats, a subcalorigenic dose ofL-T4 (at least fifty times less than those usedto stimulate protein synthesis) partly correctedthe excessive respiratory control in liver mito-chondria 3 hr after injection (Hoch, 1966). Alarger dose did the same when the rats werekilled 2 min after injection (Hoch, 1967, 1968b).The hormone content of mitochondria, as mea-sured by the total iodine or the butanol-extractable iodine, was 20% of normal in un-treated hypothyroid rats, and rose progressivelywith the functional changes up to 3 hr afterinjection (Hoch, 1967; Dillon & Hoch, 1968); theamount of hormone was one to five moleculesper respiratory assembly in the treated rats, andabout 50 /uM in the mitochondrion (a concen-tration effective in vitro in Sokoloff's experi-ments). This early or instantaneous action of thehormone was completely reversed when bovineserum albumin was added to the mitochondria,and the greater part of the hormone was therebyremoved (Hoch & Motta, 1968). The featuresof the reversibility of the functional changesdemonstrated the following: (a) that the hor-mone acted directly on mitochondria, but per-haps through an intermediate or synergisticallywith endogenous mitochondrial components; (b)that synthesis of a mitochondrial protein wasnot involved; and (c) that observations (Tata etal., 1963) that the hormone produced new mito-chondrial enzymes demonstrated an effect andnot an action of the hormone, because thoseworkers had routinely added bovine serum al-bumin to their assay mixtures and so had ob-served only the late irreversible effects of L-T3.At the present time, the actions and the effects

of the thyroid hormones appear to be relatedas in Fig. 3. Low doses of the hormone act

t-RNA-AAT = Mitochondrion Ex=>

? ? ?_

--. Ribosome => Protein synthesisNucleus- -

2 min/n v/vo

Time

FIG. 3. Sequence of events after injecting hypothyroidrats with thyroid hormone (T = L-T4), according toHoch and co-workers.

rapidly or instantaneously, and reversibly, onmitochondria (only liver mitochondria have sofar shown unmistakable results of treating hypo-thyroid rats with the hormone). The functionalchanges in mitochondria accelerate, by a process

not yet clear, the rate of translation of t-RNA-amino-acyl complexes by ribosomes to synthesizeproteins. Among the proteins synthesized arethe enzymatic components of the mitochondrialrespiratory chain. The nucleus is also involvedearly, but the relation between the rises in nuclearRNA-metabolism and the earlier changes inmitochondrial function, as well as the laterchanges in ribosomal metabolism and mitochon-drial composition, are also not yet finally de-fined. Thus, mitochondria show changes in func-tion dependent upon the hormone's presence orabsence, and changes in enzyme content secon-dary to the alterations in protein synthesis thatdepend ultimately upon the functional changes.

It now appears profitable to consider mito-chondrial respiration and energy-transformationas the loci at which the thyroid hormone nor-mally acts, and at which excess or deficiency inhormone content exerts its primary action.

Early functional changesMitochondria may be regarded as energy

transforming or transducing machines perform-ing oxidative phosphorylation: liberating energyby oxidizing a substrate, and transforming thisenergy into a chemically utilizable form forendergonic reactions, the high-energy phosphatebonds of adenosine-triphosphate (ATP). Themolecular events of this process are the subjectof intensive investigation (see Lehninger, 1964;Racker, 1965) but are as yet incompletely under-stood. Oxidative phosphorylation is measured bythe rate of oxygen consumption (energy inputper unit of time) and the efficiency of energytransfer, the P:O ratio (utilizable energy outputper energy input). The amount of work themachine can do per unit of time (the utilizableenergy output per unit of time) is in physicalunits, power. The useful output of the mito-chondrion, its oxidative power, consists of high-energy phosphate bonds.

Physiologically, the most important feature ofoxidative phosphorylation is that it is self-regulat-ing. The rate of output of high-energy phos-phate bonds controls the rate of input, i.e. theconsumption of oxygen and the oxidation ofsubstrates. ADP controls the rate of oxidation;ADP accepts the high-energy phosphate groupsfrom a hypothetical mitochondrial intermediateto form ATP. In the absence of added ADP,or in the absence of any agency removing theterminal phosphate groups of ATP to form ADP,mitochondria oxidize substrates very slowly(State 4) as in Fig. 4. Addition of ADP, or thepresence of an enzyme system hydrolysing ATPto ADP, increases the rate of oxidation markedly

349copyright.



j.bmj.com

/P


j.44.511.347 on 1 May 1968. D

ownloaded from

http://pmj.bmj.com/

350 Frederic L. Hoch

(State 3) as in Fig. 5. The respiratory controlratio is the ratio of the rates of respiration inState 3: State 4. The mitochondria in restingliving cells function as if little ADP were avail-able; that is, cells respire in State 4, in a con-trolled condition in which large demands forutilizable energy (production of ADP) can bemet with bursts of high oxidative activity (seeHoch, 1968b).

H2 X P

tsA )SH2

Oxidation Phosphorylation

FIG. 4. Normal mitochondrial oxidative phosphorylationin State 4, with no P-acceptor. The - X P groupexerts a braking effect on the oxidation cycle.

ADPH2O° (

')ATP

PiSH2

FIG. 5. Normal oxidative phosphorylation in State 3, inthe presence of ADP. The free -X group exerts nobraking effect on the oxidation cycle, and oxidation isaccelerated.

The efficiency of phosphorylation, the P:Oratio, is the number of moles of high-energyphosphate produced per gram atom of oxygenconsumed. This ratio is 3 for most compoundsoxidized via diphosphopyridine-nucleotide-depen-dent dehydrogenases. The translation of theenergy liberated by oxidation into phosphoryl-bond energy has been termed 'coupling' bymechanical analogy (Loomis & Lipmann, 1948).Phosphorylation can be decreased or abolishedselectively without diminishing mitochondrial oxi-dations. Physical agencies (e.g. heat or hypotoni-city) or a variety of chemical agents (the classicalone is 2,4-dinitrophenol) 'uncouple' oxidativephosphorylation, and decrease the phosphoryla-tion quotient by decreasing its numerator. Manyof the chemical agents also uncouple in vivowhen administered to normal animals, i.e. the

mitochondria subsequently isolated from thetreated animal phosphorylate with decreased effi-ciency.The efficiency of oxidative phosphorylation

also controls the oxidative rate. Uncouplingraises the respiratory rate markedly (State 3u),and depresses the respiratory control ratio (Fig.6); addition of ADP does not then acceleratethe already rapid respiration. Low concentrationsof uncoupling agents, insufficient to decrease theefficiency of phosphorylation measurably, alsoincrease oxygen consumption and lower respira-tory control; this is termed 'loose coupling' (Fig.7). The mechanism that ordinarily limits the rateof respiration when ADP is absent (i.e. when-X,-.P remains undischarged) now permits bothrapid respiration and transfer of energy.

H 0 ;

°2 / j

02

SH2

FIG. 6. Uncoupled oxidative phosphorylation in theabsence of ADP (State 3u). The -X group exerts nobraking effect on the oxidation cycle. Adding ADP willnot accelerate oxidation. Phosphorylation is abolished(efficiency = 0).

H20° Pf

02p

SH2

FIG. 7. Loose-coupled oxidative phosphorylation in theabsence of ADP (State 4). The - X P group nowexerts no braking effect on the oxidation cycle. AddingADP will not accelerate oxidation. Phosphorylation isat almost normal efficiency.

L-T4 and L-T3 can act like uncoupling agentsin many respects. Large doses in vivo and highconcentrations in vitro uncouple oxidative phos-phorylation (see Hoch, 1962b; Hoch & Lipmann,1954; Maley & Lardy, 1953; Martius & Hess,1952). By either route, the hormone acceleratesthe State 4 oxidation of most substrates and de-presses the respiratory control. Much smallerdoses or concentrations also lower respiratory

copyright. on M


http://pmj.bm

j.com/

Postgrad M


ay 1968. Dow

nloaded from

http://pmj.bmj.com/

Biochemistry of hyperthyroidism and hypothyroidismcontrol by raising State 4 oxidation, but theydo not depress the P: ratio (see Fig. 7), norinterfere with the inhibitory action of oligomycin(Hoch, 1968b), an agent specific for phosphory-lating respiration.

Mitochondria from hypothyroid animals, thatcontain only 20% of the normal amount ofthyroid hormone, are 'over-coupled', respiringtoo slowly in State 4 with excessive respiratorycontrol (Maley & Lardy, 1955), as in Fig. 8. It

H2 0 =

02 - %PpSH2

FIG. 8. 'Over-coupled' oxidative phosphorylation inState 4. The - X - P group now exerts a greater thannormal braking effect on the oxidation cycle. AddingADP will accelerate oxidation to (almost) normallevels. Phosphorylation is normal.

seems that the optimal amount of L-T4 is neces-sary to poise mitochondrial energy-transfer be-tween inertia and inefficiency.

Consideration of oxidative power as an indexof the performance of the mitochondrial mech-anism offers a basis for rationalizing many ofthe diverse effects of the thyroid hormones. InFig. 9, oxidative power is viewed as a resultantof changes in the rate of oxidation and/or theefficiency of energy transfer (Hoch, 1962a,1968a). The rate of energy consumption (the

% ofnormal

-P/ 10

9Q02 /_o_ /

DNP:

ThyroidstatePower(-P/t)

Energy/ consumed

/ (Q02)/

Efficiency(NP/0)

O ==Cr-

-Hypo -Eu Hyper --

j-- I-FIG. 9. Fuel consumption (Qo,), efficiency (- P:O),and power (- P:t) of the mitochondrion as a functionof the concentration of DNP or thyroid hormone (fromHoch, 1968a).

Qo2) and the efficiency of the machine (the,PP:O ratio) are plotted as a function of theconcentration of an agent that can uncouple,e.g. DNP or thyroid hormone. It will be seenthat low concentrations of DNP or thyroid hor-mone stimulate energy consumption before effi-ciency is depressed; the result is increased power.Higher concentrations uncouple and depressefficiency. Power therefore is decreased, and itis this catabolic effect that is seen in thyrotoxi-cosis. In hypothyroid subjects, mitochondrialenergy consumption is depressed below normal,but efficiency is normal. Power is therefore de-creased. Treatment with L-T4 raises energy con-sumption, but does not affect efficiency: poweris restored to normal, an anabolic action. DNPhas been shown to possess such an anabolicaction as well, in accelerating protein synthesisin vitro (Sokoloff & Kaufman, 1961).However, the differences between the thyroid

hormones and the uncoupling agents should bestressed at this point: certain effects of the thy-roid hormones are biologically specific. Agentslike DNP do not relieve all the defects seen inhypothyroid subjects, nor do they stimulategrowth and development, nor do they inducemetamorphosis in Anura. The specificity mustreside in the differences between their actions atthe mitochondrial level. The mechanisms ofaction of thyroxine and DNP are known todiffer: thyroxine makes mitochondria swell andDNP does not; and thyroxine and DNP actsynergistically on mitochondrial respiration, notadditively.At least two factors may govern the effect

of thyroid hormones: the thyroid state of theorganism (presumably a function of the concen-tration of thyroid hormone in contact with thetarget sites) and the additional amount of theadministered hormone reaching the target. Thus,thyroid hormone given to a hypothyroid subjectraises oxidative metabolic power to normal levels;similar dosage in a euthyroid subject increasespower above normal; higher dosage decreasespower.

Late compositional changesThe functional changes in mitochondrial res-

piration discussed in the previous section involvespecific respiratory activity, in the sense of therate of respiration per amount of respiring mass.The thyroid hormones also affect the total res-piratory mass in the mitochondrion. They con-trol, through protein synthesis, the amount ofrespiratory enzymes per gram of total proteinin the mitochondrion. In hypothyroidism, therate of protein synthesis is lower than normal.

351copyright.



j.bmj.com

/P


j.44.511.347 on 1 May 1968. D

ownloaded from

http://pmj.bmj.com/

Frederic L. Hoch

Mitochondria from hypothyroid rats containhalf as much cytochrome b, c, and a+a3 as nor-mal mitochondria (Maley, 1957; Kadenbach,1966) and perhaps less flavoprotein catalysts (Riv-lin & Langdon, 1966). But, paradoxically, thereis twice the normal amount of pyridine nucleo-tide coenzymes. Conversely, in mild hyperthyroid-ism, with its raised rate of protein synthesis,the content of cytochromes and flavoproteins ishigh, and of pyridine nucleotides, low (Kaden-bach, 1966; Maley & Lardy, 1955).At first glance, these compositional differences

seem to reflect or account for the abnormalBMRs in thyroid disease. However, the situationis not so clear. The flavoproteins and cyto-chromes have turnover numbers, and are pre-sent in such amounts in mitochondria, that theydo not control or limit oxidation in the respira-tory chain. The 'bottle-neck' in respiration (actu-ally in electron-transport) appears to be at ornear the pyridine nucleotide end of the chain(Chance, 1965), and there is evidence that thesubstrate-dehydrogenase interactions are involved(Klingenberg, 1963). The pyridine nucleotides,however, change in amount in a direction oppo-site to the changes in BMR, under thyroid hor-mone influence. Thus, while the hormone seemsto control the maximal capacity for oxidation inmitochondria, it also controls the specific acti-vity of respiration in the chain, and the latteraccounts for the rate of oxygen consumption inthe resting subject (Ernster & Luft, 1964). Theimportance of capacity for oxidation in pro-cesses involving large demands for energy, how-ever, should not be minimized.The resting hyperthyroid subject thus con-

sumes oxygen faster because the mitochondriain his tissues consume oxygen faster in State 4.The term 'hypermetabolism' in this connection isa misnomer, for while oxidation is increased, themetabolic processes of phosphorylative energytransfer are normal or decreased. This kind ofhyperoxidation arises from the presence of ex-cess amounts of thyroid hormones in the mito-chondria. Not all organs consume more oxygenin thyrotoxic subjects; the brain, spleen andtestes do not. The mitochondria of brain, spleenand testes do not swell in the presence of thyroidhormones, in contrast to those from other tissues(Tapley & Cooper, 1956), but it is not knownif their iodine contents are high or normal inthyrotoxic subjects. Another kind of hyperoxi-dation may arise from the late adaptive increasesin mitochondrial enzyme content, but it is pre-sumably fully efficient and should persist forsome time even when the amount of thyroidhormone in the mitochondria becomes normal.

The increased rates of oxidation are accom-panied by increased production of heat per unitof time even when efficiency is normal, and rela-tively more heat than utilizable energy will beevolved as the efficiency of energy transfer de-creases. In the most extreme forms of thyro-toxicosis, where more complete uncoupling mightoccur, heat production leads to hyperpyrexia (asin thyroid crisis; see below). Lesser degrees ofheat production are compensated by sweating,vascular changes, dilation, flushing, and resultanttachycardia, increased cardiac stroke volume andpulse pressure. Such changes may in part bemediated through the action of the hormonesof the adrenal medulla (see pp. 357-8). Compen-sation may be precarious, and the excessive de-mands imposed by relatively slight increases ofexternal temperature, the rise of heat produc-tion during muscular exercise, or administrationof agents with uncoupling properties may havedrastic consequences. Increased tissue heat em-phasizes the increased metabolic demands andfurther accelerates oxidative rate. Weight lossand wasting of both fat and lean body mass(Wayne, 1960) occur without any losses inappetite.

Conversely, the hypothyroid subject consumesoxygen more slowly than normally because hismitochondria respire slowly in State 4. Both be-cause of thyroid hormone deficiency and res-piratory enzyme depletion, 'hypometabolism' ishere not a misnomer, phosphorylative metabolismproceeding at a low rate because of thediminished liberation of oxidative energy. De-creased rates of oxidation produce less heat, andextremes result in hypothermia (see myxoedemacoma, below). Demands for increased heat pro-duction, as in acclimatization to cold environ-ments, are met poorly by hypothyroid subjects.Responses to the hormones of the adrenalmedulla are subnormal. It is of some interestthat clinical investigators (Selenkow & Marcus,1960) have commented upon the 'apathetic'hyperthyroidism seen in older patients. It hasfeatures similar to those of hypothyroidism; onour basis, both are reflections of the decreasedcapacities for the production of utilizable energy.Alterations in metabolism

Certain features of clinical and experimentalhyperthyroidism and hypothyroidism may beconsidered as manifestations of changes in thetransformation of energy. More information isavailable on the correlation of manifestationsand basic changes in hyperthyroidism than inhypothyroidism. The following are those areasof energy utilization best studied at present.

352copyright.



j.bmj.com

/P


j.44.511.347 on 1 May 1968. D

ownloaded from

http://pmj.bmj.com/

Biochemistry of hyperthyroidism and hypothyroidismProtein metabolismThyroid hormones control protein synthesis

and breakdown. The effect of administered thy-roid hormones depends upon the thyroid statusof the subject. Low doses of thyroxine stimulateprotein synthesis, high doses depress it. L-Tsdecreased protein synthesis in euthyroid humans,but the same dose raised the low rate of proteinsynthesis to normal levels in myxoedematouspatients (Crispell, Parson & Hollifield, 1956). Inhypothyroid rats, 5-10 ,ug of T4 daily increasedprotein synthesis (Karp & Stetten, 1949; Rupp,Paschkis & Cantarow, 1949), but in either hypo-thyroid or normal animals, 50-100 j/g decreasedor abolished synthesis (Rupp et al., 1949; Soko-loff & Kaufman, 1959). Hyperthyroid humanshave subnormal amounts of parenchymal pro-tein in liver biopsies (Nikkila & Pitkanen, 1959).Consistent with the decreased synthesis of pep-tide linkages, the concentrations of free aminoacids in blood, liver and muscle are elevated inthyrotoxic rats (Crispell et al., 1956; Friedberg& Greenberg, 1947). Rat muscle (Ferrini, Per-roni & Bestagno, 1959) and human cells growingin culture (Leslie & Sinclair, 1959) incorporateamino acids into proteins more slowly in thepresence of added thyroxine. Sokoloff & Kauf-man's (1961) studies have demonstrated in vitrothat the apparently conflicting effects of T4 uponprotein synthesis are in reality biphasic hor-monal effects.

Lipid metabolismThyroid hormones control the rates of lipid

synthesis, oxidation and mobilization. Biphasiceffects of thyroid hormone have been shown onlipid synthesis (Fletcher & Myant, 1960); 20 /ugof thyroxine increased the synthesis of choles-terol from acetate by the cell-free fractions ofrat livers, while 30-50 /,g decreased the syn-thesis. Fatty acid synthesis was decreased at allthese levels of dosage.

Thyroid-treated rats and humans synthesizedcholesterol more rapidly than normal (Kritch-evsky, 1960), and the hypocholesterolaemia ofthyrotoxicosis, anomalous in the face of increasedsynthesis, was ascribed to the hormonal stimu-lation of cholesterol excretion (Rosenman, Byers& Friedman, 1952). Increased rates of choles-terol and fatty acid synthesis have been ob-served in hormone-treated rats and in their tissueslices (Karp & Stetten, 1949; Dayton et al, 1960).On the other hand, decreased rates of choles-terol synthesis were observed in liver homo-genates (Scaife & Migicovsky, 1957) and cell-free preparations (Fletcher & Myant, 1962) fromthyrotoxic rats. The cholesterol and neutral fat

contents of the livers of thyroxine-treated rats(Handler, 1948), and the fat content of humanbodies (Wayne, 1960) were below normal inhyperthyroidism. Thyroidectomy also decreasedthe rate of cholesterol synthesis (Boyd, 1959);the low rate of synthesis of cholesterol and fattyacids in myxoedematous subjects was raised tonormal by thyroid hormones (Lipsky et al., 1955)However, the control of lipid synthesis by thy-roid hormones has also been observed in tissuepreparations that were supposed to be free ofmitochondria (Fletcher & Myant, 1960).The defects and increases in lipid synthesis

might be ascribed to changes in the availabilityof ATP at various steps in the process, even ifmitochondria were not present in the lipid-synthesizing preparations. Thus, the effects ofthyroid hormones have been laid to alterationsin the supply of acetyl-coenzyme A, or furtheralong the synthetic path, in the conversion ofacetate to cholesterol, fatty acids and CO2 (Day-ton et al., 1960); both require ATP. Coenzyme Aconcentrations do vary in the tissues of thyro-toxic animals, being low in hyperthyroid ratlivers (Fraenkel-Conrat & Greenberg, 1946) andin hyperthyroid humans (Gershberg & Kuhl,1950), and rising above normal when thyroidec-tomized rats are treated with thyroxine, appar-ently via increased availability of ATP (Tabach-nick & Bonnycastle, 1954).The fatty acid oxidases are in mitochondria.

Thyroid hormones can act directly on lipid oxid-ations by controlling ATP production, since fattyacid activation requires ATP prior to oxidation.Thyroxine treatment accelerated fatty acid oxid-ation in rat heart homogenates (Deitrich & Smith,1960), earlier than it raised the basal metabolicrate (Abelin & Kiirsteiner, 1928). Bacterial oxid-ation of cholesterol was increased by addedthyroid hormones (Wainfan & Marx, 1955).Hypothyroidism decreased fatty acid oxidationand ATP production from fatty acids in thehearts of dogs.Thyroid hormones also control fatty acid con-

centrations in tissues through the rate of themobilization of fatty acids from adipose tissue,in conjunction with the action of other hor-mones. T3 and Triac raised serum concentra-tions of unesterified fatty acids within 6 hr inhumans (Rich, Bierman & Schwartz, 1959) andenhanced their release from adipose tissue andtheir removal from serum in dogs. Thesethyroid effects are facilitations of other stimuli,particularly epinephrine (Jeanrenaud, 1961),which ordinarily liberate fatty acids (Schwartz& Debons, 1959). Epinephrine-induced mobili-zation of fatty acids in vivo requires optimal

353copyright.



j.bmj.com

/P


j.44.511.347 on 1 May 1968. D

ownloaded from

http://pmj.bmj.com/

Frederic L. Hoch

thyroid function, while thyroid hormone alonedoes not release fatty acids from adipose tissuein vitro (White & Engel, 1958). Hypothyroidismprevents epinephrine-induced mobilization. Inhypopituitary monkeys epinephrine injectionliberated no fatty acids; thyroid-stimulating hor-mone partly restored, and small doses of T3fully restored, the normal fat-mobilizing res-ponse to epinephrine (Goodman & Knobil,1959). Hyperthyroidism exaggerates the epine-phrine effect on fat pads in vitro (Debons &Schwartz, 1961) and hypothyroidism abolishes it.The fat-mobilization effects of insulin are simi-larly affected by the thyroid state, insulin re-leasing six times more free fatty acids from theadipose tissue of T4-injected rats than normally(Hagen, 1960). These interdependences of hor-mone effects may reflect the facts that fat mobi-lization depends upon the production of cyclic-3',5'-AMP, and that cyclic-3',5'-AMP is formedonly from ATP; the thyroid hormones controlATP production, and it may be speculated-inthe absence of definite information to date-that the ATP supply, as well as the hormone-controlled activity of adenyl cyclase, controlscyclic-3',5'-AMP production.

Carbohydrate metabolismThyroid hormones control the rates of gly-

cogen synthesis and breakdown, and of hexoseoxidation.Thyroxine has a biphasic effect on glycogen

synthesis. Low doses of thyroxine increased gly-cogen synthesis in rat diaphragms either in vivoor in vitro, and higher doses reversed this effect(Wertheimer & Bentor, 1953). In vivo injectionsof thyroid-stimulating hormones (in normal butnot in thyroidectomized animals), or of 20-30 /ugof L-thyroxine, increased glycogen synthesis,whereas 100-200 /ug of L-thyroxine decreasedsynthesis below normal rates. In vitro, incuba-tion of 2 /ig of L-thyroxine with normalrat diaphragms increased glycogen synthesiswhile higher amounts either did not stimulate,or irregularly depressed, synthesis. Both the invitro and the in vivo effects depended upon in-cubation of the diaphragms in homologous ratserum, which may have involved thyroxine-bind-ing or lipid-binding. The lack of a measurablerise in oxygen consumption, however, indicatescaution in accepting this system as one depend-ing simply on ATP-supply.Most of the available evidence indicates de-

creased synthesis of glycogen in thyrotoxicosis.Glycogen synthesis was decreased in hyperthy-roid humans and rabbits (Coggeshall & Greene,1933; Mirsky & Broh-Kahn, 1936). The glycogen

contents of liver and muscle were markedlydiminished in hyperthyroid subjects, especiallythe metabolically active forms of glycogen (Chil-son & Sacks, 1959), but this, of course, may alsodepend on increased breakdown. Consistent witha decrease in synthesis is the fact that both liverand muscle (where the major portion of gly-cogen synthesis proceeds) showed decreased con-tents of ATP after thyroid hormones were ad-ministered (Chatagner & Gautheron, 1960; Berg,1937). Increases in synthetic rates have also beenobserved, however, after single doses (Stern-heimer, 1939) or more prolonged hormone treat-ment followed by liver perfusion with largeamounts of glucose (Burton, Robbins & Byers,1958).The hyperglycaemic effect of epinephrine,

mediated through the increased formation ofcyclic-3',5'-AMP and the subsequent activationof phosphorylase, depends upon the thyroidstate, and administered thyroid hormone pro-duces biphasic effects. A small dose of T4 raisedthe hyperglycaemic effect of injected epinephrinewhereas in rabbits fed 225 g of desiccated thy-roid, epinephrine caused little or no hypergly-caemia (Burn & Marks, 1925; Abbot & VanBuskirk, 1931). The amount of liver glycogenalso affects the hyperglycaemic response to epine-phrine; prolonged thyrotoxicosis depletes rabbitliver glycogen and then no hyperglycaemia fol-lows epinephrine administration. In hypothyro-dism, epinephrine produced a response smallerthan normal.

Thyroid hormones affect hexose oxidation andhexose phosphorylation, directly and by modifica-tions of the actions of other hormones. Oxidationof hexoses was accelerated by administered thyroidhormone, either through equal increases in boththe phosphogluconate and the glycolytic path-ways, or mainly through increased glycolysis; theroute chosen may depend upon the degree ofhyperthyroidism, low doses of hormone acceler-ating glycolysis mainly (Glock, McLean & Whitehead, 1956) and depressing the phosphogluconatepath (Dow & Allen, 1961). Hypothyroidism de-pressed glucose exidation via both paths (Dow& Allen, 1961). The mechanisms of the thyroidhormonal effects on glycolysis may be via oneor more routes. An effect of thyroxine on thecytoplasmic acylphosphatase of rat liver andmuscle has been demonstrated: administeredhormone increases acylphosphatase activity, thy-roidectomy decreases it, and then low doses ofT4 restore it (Harary, 1958). This enzyme hydro-lyses 1,4-diphosphoglycerate to Pi and 3-phos-phoglycerate; it acts as a rate-limiting ATPase,uncoupling glycolysis from phosphorylation, and

354copyright.



j.bmj.com

/P


j.44.511.347 on 1 May 1968. D

ownloaded from

http://pmj.bmj.com/

Biochemistry of hyperthyroidism and hypothyroidismaccelerates both glycolysis (by supplying Pi) andmitochondrial oxidation (by supplying ADP).And the activity of two enzymes of the glyco-lytic pathway, enolase and lactic dehydrogenase,were increased in the livers of thyrotoxic rats(Bargoni et al., 1961), but they are probably notrate-controlling steps; the activities of a numberof the glycolytic enzymes were decreased in hypo-thyroidism (Bargoni et al., 1964). Lastly, thehormonal control of the generation of NADHand NADPH by mitochondria might also affectboth glycolysis and the phosphogluconate path-way (Dow & Allen, 1961). Increased glucoseuptake or oxidation, or both, have been ob-served in the muscles and in the livers of hyper-thyroid animals, and also in cultures of animalcells, sperm, Saccharomyces cerevisiae, or Ace-tobacter aerogenes treated with thyroid hormones.The rates of glucose utilization may also be

affected through a hormonal control of hexosephosphorylation. Thyrotoxicosis raised the acti-vity of intestinal phosphokinases (Nishikawara &Gabrielson, 1961), and the observed delays inthe tolerance curves for glucose and galactosein this condition have been ascribed to rapidphosphorylation and intestinal absorption (Alth-ausen, 1940). However, the importance of thephosphokinases in absorption has been ques-tioned (Nishikawara & Gabrielson, 1961). Theutilization rate of glucose, measured under con-stant intravenous load, is reported to be normalin thyrotoxicosis (Macho, 1958) and normal inhypothyroidism (Macho, 1961); in hypothyroid-ism, administration of thyroxine or DNP rapidly(4 hr) accelerated the utilization rate, suggestingthat these two agents act similarly.

Intravenous glucose-tolerance tests gave highdisappearance rates in hyperthyroid patients andlow rates in hypothyroids; tolbutamide decreasedblood glucose faster in hyperthyroids and slowerin hypothyroids; and glucagon induced a lowerglucose response in hyperthyroids (Lamberg,1965). Orally administered D-xylose was norm-

ally absorbed by patients with thyrotoxicosis or

myxoedema, but oral or intravenous D-xylosewas excreted in the urine more rapidly in thyro-toxicosis, and less rapidly in myxoedema (Broit-man et al., 1964). Thyroid hormones potentiateinsulin action; insulin-induced hypoglycaemia wasincreased in human thyrotoxicosis (Elrick, Hlad& Arai, 1961), and the uptake of glucose by ratadipose tissue was more sensitive to insulin afterthyroxine was injected (Hagen, 1960).

Muscle contraction and creatine metabolismThyroid hormones control muscle contraction

and creatine metabolism. In human hypothyroid-

ism, skeletal muscles are larger and firmer thannormal and contract slowly because of an ab-normality in the contraction mechanism (Milli-kan & Haines, 1957). The clinical sign of the'hung-up' reflex, with its slow relaxation, reflectsthis defect. In hyperthyroidism, muscle contractsat the normal rate, but performs work ineffi-ciently (Plummer & Boothby, 1923). Clinically,'thyrotoxic myopathy' (Thorn & Eder, 1946; Hed,Kirstein & Lundmark, 1958) reflects this defect.Thyroxine has a biphasic effect on muscularwork in adrenalectomized rats, a low dose im-proving the work done per contraction, and afour-times-higher dose decreasing it (Ganju &Lockett, 1958).The relation between muscle contraction and

thyroid state thus seems clearer than in the caseof some of the synthetic processes, probably be-cause muscle contraction and relaxation dependmore directly upon ATP supplied by mitochon-drial oxidative phosphorylation. The other sourceof muscle ATP, the r-P of phosphocreatine, cansupport only a few contractions and must itselfbe replenished from mitochondrial energy trans-formations. The skeletal muscles of thyrotoxicrats showed uncoupling (Johnson et al., 1958),and those of thyrotoxic humans showed loosecoupling (Ernster, Ikkos & Luft, 1959). In ourterms, these mitochondria showed the action ofthe excessive amounts of thyroid hormones pre-sent. Other studies on apparently similar patientshave shown normal muscle mitochondrial res-piratory control, and either high controlled (State4) and maximal (State 3) respiration (Stocker,Samaha & De Groot, 1966) or normal levels ofrespiration (Dow, 1967; Peter & Lee, 1967); be-cause bovine serum albumin was used in thepreparation and assay of the mitochondria, theseresults may show only the underlying enzymaticcomposition of the muscle mitochondria as con-trasted with the action of the excessive amountsof hormone present in situ.Heart muscle mitochondria are particularly

susceptible to thyroid hormones (Bing, 1961).Clinically, this seems to be reflected in the highincidence of myocardial failure in thyrotoxicosis(the increased work load and decreased effi-ciency of contraction are an unfortunate com-bination), and in the lack of response of thisform of failure to digitalis (which is more effec-tive against mechanically induced defective con-tractile mechanisms).

Alterations in creatine metabolism usually in-volve muscle. A rationale for the observationsis shown in Fig. 10. Clinically and experimentally,hyperthyroidism is accompanied by increasedcreatine excretion, and hypothyroidism by de-

355copyright.



j.bmj.com

/P


j.44.511.347 on 1 May 1968. D

ownloaded from

http://pmj.bmj.com/

Frederic L. Hoch

creased creatine excretion. In hyperthyroidism,creatine synthesis was normal (Wilkins & Fleisch-mann, 1946). Injection of thyroxine rapidly de-pleted muscle phosphocreatine content, well be-fore creatine excretion rose (Wang, 1946), sug-gesting a hormonal effect of phosphorylation.Thyrotoxic humans excreted creatine admini-stered to them, or endogenously synthesized, incontrast to normal subjects, because of an in-ability to 'fix' creatine in their muscles, i.e. toresynthesize phosphocreatine from creatine andATP (Shorr, Richardson & Wolff, 1933; Thorn,1936). The defective creatine load-test is so char-acteristic that it has been used diagnostically.

ADP

C-* ATP,I MuscleAT PC * contraction

Pi ---Pi +Cr

^ 1[E xcretion

FIG. 10. Creatine and inorganic phosphate ion meta-bolism in relation to mitochondrial energy transfer.Creating phosphate (Cr - P), usually in equilibriumwith the generated ATP, dissociates in hyperthyroidismto maintain the ATP level. The extra free creatine (Cr)and phosphate (Pi) are excreted. The Pi pool is aug-mented through inefficiency of oxidative re-esterification.Similarly, administering extra Cr in a load test augmentsthe Cr-pool and subsequent excretion.

Vitamin metabolismThe thyroid hormones control the utilization

of the water-soluble vitamins and their synthesisinto coenzymes. The synthetic steps affected areusually energy-requiring condensations and phos-phorylations. Most of the information is avail-able on thyrotoxic subjects, where conditionedvitamin deficiences exist (Drill, 1943; Rawson,Rall & Sonenberg, 1955). Normal intake of vita-mins is accompanied by deficiency symptomsbecause of increased demands or defective utili-zation.Thiamine requirements are increased in hyper-

thyroid patients. The blood and liver vitamincontents were subnormal, and the excretion washigher than normal (Williams et al., 1943). Tis-sue cocarboxylase content was low in hyper-thyroid rats; it rose after thiamine was injected,but then fell more rapidly than in euthyroidanimals, suggesting rapid destruction (Peters &Rossiter, 1939). Pyridoxine availability is limitedin the tissues of hyperthyroid animals (Wohl et

al., 1960). Pyridoxal-5-phosphate content was lowbecause of defective phosphorylation; conversely,it was high after thyroidectomy (Labouesse,Chatagner & Jolles-Bergeret, 1960). VitaminB12 content was low in the tissues of thyro-toxic rats and hypothyroid female rats (Gershoffet al., 1958; Kasbekar et al., 1959); hormoneadministration raised renal B12 to normal inhypothyroid rats, and above normal in euthy-roid rats (Okuda & Chow, 1961). Ascorbic acidcontent was low in the blood and tissues ofthyrotoxic subjects. Pantothenic acid and CoAmetabolism have been discussed under 'Lipidmetabolism', and follow the same general pat-tern as the other water-soluble vitamins.The thyroid hormones also control the syn-

thesis of a fat-soluble vitamin. Vitamin A syn-thesis requires thyroid hormone. Both hypo- andhyperthyroid patients had poor dark adaptation(Wohl & Feldman, 1939). In hypothyroidismserum vitamin A was decreased because carotenewas not converted to the vitamin; hormone treat-ment restored synthesis (Drill & Truant, 1947;Johnson & Baumann, 1947). In euthyroid animals,the hormone increased vitamin A synthesis, butprolonged treatment produced a severe resistantvitamin A deficiency (Portugal'skaya, 1961), an-other example of the hormone's biphasic effect.

Metabolism of inorganic ionsPhosphorus metabolism is strongly influenced

by the thyroid state. Hyperthyroid patients arein negative phosphorus balance (Rawson et al.,1955). Hypothyroid patients excreted largeamounts of phosphate soon after administrationof the hormone, probably because of increasedphosphocreatine hydrolysis (Beaumont, Dodds &Robertson, 1940; Flach et al., 1959). Phosphatecontents were high, and ATP contents were low,in the soft tissues of thyrotoxic animals (Berg,1937; Chatagner & Gautheron, 1960; Maley,1957). The esterification of phosphate was slowin such tissues (Johnson et al., 1958). In thebones of hyperthyroid patients, phosphate wasturned over abnormally rapidly (Hernberg, 1960)probably in conjunction with the changes incalcium.

Calcium metabolism also changes in thyroiddisease. Calcium turnover in bones is acceleratedin hyperthyroid patients, and becomes normalwith the thyroid state upon treatment (Kraneet al., 1956). Calcium accumulation was morestriking in the livers than in the bones of thyro-xine-treated rats; the capacity of liver mitochon-dria to store Ca++ may be involved. In hypo-thyroid rats, calcium incorporation into bonewas decreased (Lengemann, Wasserman &

356copyright.



j.bmj.com

/P


j.44.511.347 on 1 May 1968. D

ownloaded from

http://pmj.bmj.com/

Biochemistry of hyperthyroidism and hypothyroidism

Comar, 1960) but in hypothyroid humans, hor-mone administration did not raise calcium ex-cretion rapidly, although it raised phosphate ex-cretion (Beaumont et al., 1940), perhaps becausethe hormone acts more directly on phosphatemetabolism.Magnesium metabolism depends upon the

thyroid state, and vice versa. Mg++ and thyroidhormones are antagonists in vivo and in vitrowhen mitochondrial function is measured (seeHoch, 1962b). Myxoedematous patients excretedlarge amounts of Mg++ in their urine promptlyafter hormone administration (Tapley, 1955). Theplasma magnesium content was low in hyper-thyroidism and high in hypothyroidism; Mg bal-ance was positive in hyper- and negative inhypothyroidism; total and cellular exchangeableMg++ was strikingly low in hypothyroidism butnormal in hyperthyroidism (Jones et al., 1966).The effect of administering magnesium salts uponthyrotoxicosis is controversial, some finding adecrease in BMR and heart rate (Hueber, 1939),others finding no decrease in BMR nor changein negative nitrogen and phosphate balancesWiswell, 1961).

Decreased exchangeable potassium (Munro,Renschler & Wilson, 1958; Wayne, 1960) andhyperkalaemia and hyperkaluria (Boekelman,1948) have been reported in thyrotoxicosis. Oc-casionally periodic muscular paralysis is asso-ciated with hyperthyroidism.

Temperature regulationThe thyroid hormones are involved in the

control of body temperature. About 60% of theenergy liberated by mitochondrial oxidations isnormally converted to a chemically utilizableform, the other 40% being liberated as heat andthereby maintaining the body temperature ofhomeotherms. In hyperthyroidism heat produc-tion is raised by two factors: the increased rateof oxidation and the decreased efficiency ofenergy conversion. Usually the excess amountsof heat can be dispelled by physiologic com-pensations such as flushing, sweating and in-creased circulation; many of the clinical char-acteristics of hyperthyroid patients arise fromthese compensations.

Thyrotoxic crisis or storm can be viewed as afailure of compensation due to increased heatproduction through a further loss of mitochon-drial efficiency. Body temperatures rise sharplyto 107°F or more, muscle tone is lost, liverdamage (? mitochondrial) is severe and thepatients may die. Body refrigeration may removeenough heat to save the situation, but therapeuticmeasures to provide adrenocortical hormones

and to antagonize adrenomedullary hormoneshave also been used with success.The experimental induction of the acute

hyperthermia that is seen clinically in thyroidcrisis provides an insight into how the thyroidhormones act physiologically. Administering largedoses of thyroid hormone to animals usuallyproduces a loss of weight and an apathetic death,not a hyperthermic crisis. Much smaller dosesof hormone, however, can produce fatal hyper-thermia in conjunction with the administrationof an agent that acts on mitochondrial oxidativemetabolism. Among such compounds are the un-coupling agents, like dinitrophenol (Hoch, 1965a)dinitro-o-cresol (Barker, 1946) and methyleneblue (Alwall, 1936); phosphate ions given by in-fusion (Roberts et al., 1956); and antipyreticagents, like sodium salicylate (Hoch, 1965a). Adose of salicylate too small to raise the BMRin a normal rat raises the BMR sharply in amidly hyperthyroid rat; one-quarter of the nor-mally lethal dose of salicylate rapidly inducesa fatal hyperthermia in such hyperthyroid rats.With dinitrophenol, this phenomenon can beshown to arise from an exaggerated sensitivityof mitochondria to the uncoupling agent, in-duced by thyroxine treatment (Hoch, 1968c).Whether the clinical phenomenon has a similarbasis remains to be seen. The association ofthyroid crisis in thyrotoxic patients with infec-tions that cause fever (Means, De Groot & Stan-bury, 1963) may be another example of an invivo synergism.

In hypothyroidism, heat production isdiminished by the depressed rate of mitochon-drial oxidations. Again there are physiologiccompensations to preserve body heat, and theskin is cold, circulation is slow, and cold ispoorly tolerated. Body temperatures may bebelow normal. Infections that normally elicitfever may not raise the hypothyroid patient'stemperature at all, or at least not above normal.Occasionally a fatal hypothermia may supervene,the so-called myxoedema coma, in which bodytemperature can no longer be maintained, andhas been reported as low as 74°F. Experiment-ally the calorigenic response of hypothyroid ratsto an administered uncoupling agent is sub-normal (Hoch, 1965b), because their mitochon-dria are subnormally sensitive (Hoch, 1967,1968c). Administered thyroxine rapidly raisesmitochondrial responses, and the efficiency ofsuch treatment clinically may be evidence for acommon basis for the hypothermia.Effects of hormones and drugsThe effects of a number of hormones and

357copyright.



j.bmj.com

/P


j.44.511.347 on 1 May 1968. D

ownloaded from

http://pmj.bmj.com/

Frederic L. Hoch

drugs depend upon the thyroid state of the sub-ject, as has been mentioned above in connec-tion with specific systems. In general, hyper-thyroidism exaggerates and hypothyroidism min-mizes the changes seen after administration ofthe agent. Physiologically, the clearest exampleis that of the catecholamines. The relationshipis so striking that some have concluded that theapparent peripheral effects of thyroxine areactually effects of epinephrine (Brewster et al.,1956), but there is evidence against so sweepinga claim (see Hoch, 1962b). The biochemicalbasis of the observed interdependences may bethe inactivating effects (or actions?) of thyroidhormones upon the enzymes that normally in-activate the catecholamines themselves. The cate-chol-o-methyl-transferase (D'Iorio & Leduc,1960), the amine oxidases (Zile & Lardy, 1959),and a peroxidase system (Klebanoff, 1959) havebeen studied, but it is still difficult to assignphysiologic relevance to the mechanisms.Another enzymatic system under scrutiny in thisregard involves the formation of cyclic-3',5'-AMP, the mediator of many of the catechol-amine effects. Thyroid hormones have been sug-gested to control the activation of the lipase inadipose tissue via a mechanism involving cyclic-3',5'-AMP (Fisher & Ball, 1967). Yet other pos-sible routes are the control the thyroid hormonesexert over ATP availability, since ATP is theonly source of cyclic-3',5'-AMP; and the sen-sitivity of mitochondria. Adrenochrome andthyroxine act synergistically on mitochondria invitro (Park, Meriwether & Park, 1956). Theglycogenolytic and hyperglycaemic, the lipolytic,the inotropic, and the calorigenic effects of epine-phrine all depend upon the thyroid state (seeEllis, 1956; Brodie et al., 1966; Goodman &Bray, 1966). The abnormally slow pulse rateafter epinephrine administration in hypothyroidpatients, and the rapid rate in hyperthyroid sub-jects, have been used diagnostically, althoughcaution is advised in hyperthyroids (Goetsch &Ritzmann, 1934).The dependence of the calorigenic effect of

epinephrine upon the thyroid state is an exampleof the generality that the thyroid state controlsthe response of the body to calorigenic sub-stances. Excessive rise in BMR is seen in hyper-thyroidism, and little or no rise is seen in hypo-thyroidism, after the administration of glucagon(Davidson, Salter & Best, 1960), nitrophenols,salicylates (Hoch, 1965a, b), chloropromazine(unpublished data), and 'febrile toxins' (above).The only exception seems to be the enhancedsensitivity of hypothyroid subjects to the thyroidhormone itself.

The adrenal cortical hormones and insulin mayhave synergistic effects with the thyroid hor-mones on a physiological level, but these effectsinvolve different rates of catabolism and produc-tion of all three groups of hormones, as wellas interactions in the tissues.

Other featuresThere are several clinical features of hyper-

thyroidism and hypothyroidism that are notreadily reduced to manifestations of changed cel-lular energy transfer. These features fall intotwo categories. First, there are those that arisefrom mechanisms not due directly to thechanged amounts of thyroid hormones in thetissues, but to phenomena associated with theprimary defect in thyroid hormone production.Thus, exophthalmos is one of the classical signsin the Merseburg triad in hyperthyroidism but itis not produced by hormone administration(Means et al., 1963). A pituitary factor, possiblyassociated with thyrotropin, may be responsible(Loeb & Friedman, 1932). The frequent persist-ence of exophthalmos after the therapeutic res-toration of euthyroidism speaks for such asecondary relationship.

In the second category are those clinical fea-tures that may (and indeed seem to) arise fromchanged amounts of tissue thyroid hormone, butthat are not reducible to cellular phenomena be-cause we don't know enough yet. The hyper-irritability of the nervous system in hyperthyroi-dism, and its opposite in hypothyroidism, maybe presenting symptoms clinically. The involve-ment of ATP in nerve conduction and in re-synthesis of acetylcholine at the myoneural junc-tion, and the involvement of K+, Ca++ and Mg++in neural events make it likely that hormone-induced defects in energy transfer and ion ac-cumulation will affect the nervous system, butjust how changes in nerve function relate to'nervousness' presents complex problems not yetconclusively approached. Similarly, the present-ing abnormality of 'myxoedema' seems to be adefect in mucopolysaccharide metabolism thatleads to excessive deposition, somehow and pre-sumably dependent upon insufficient thyroidhormone.The thyroid hormones obviously control

growth, development, and the striking structuraland chemical changes in Anuran metamorphosis.In general terms we may say these processesmust depend upon available 'energy' but ourlack of knowledge of the details of the energy-dependent steps precludes a mechanistic inter-pretation at present. In this area, however, therecent evidence that the thyroid hormones con-

358copyright.



j.bmj.com

/P


j.44.511.347 on 1 May 1968. D

ownloaded from

http://pmj.bmj.com/

Biochemistry of hyperthyroidism and hypothyroidism 359

trol mitochondrial energy metabolism directlyand promptly, and thereby regulate protein syn-thesis, offers promise of new and important in-formation on biologic and medical problems.

AcknowledgmentThis work was supported by research Grant AM-11184

from the National Institutes of Arthritis and MetabolicDiseases, National Institutes of Health, Bethesda, Maryland,U.S.A.

ReferencesABBOT, A.J. & VAN BUSKIRK, F.W. (1931) The blood sugar

response to epinephrin in thyroid-fed animals. Amer. J.med. Sci. 182 610.

ABELIN, I. & KURSTEINER, P. (1928) Ober den Einflusz derSchilddrusensubstanzen auf den Fettstoffwechsel. Biochem.Z. 198, 19.

ALTHAUSEN, T.L. (1940) The disturbance of carbohydratemetabolism in thyrotoxicosis. J. Amer. med. Ass. 115, 101.

ALWALL, N. (1936) Ober die Wirkung der Dinitrophenoleauf die Tierischen Oxydationsprozesse. Skand. Arch.Physiol. Suppl. 72, 1.

BARGONI, N., GRILLO, M.A., RINAUDO, M.T., FOSSA, T.,AYASSOT, M. & Bozzi, M.L. (1964) Glycolysis andglycogenesis in the liver of hypothyroid rats. Boll. Soc. ital.Biol. sper. 40, 1888; (Chem. Abstr., 64, 2506e, 1966).

BARGONI, N., LUZZATI, A., RINAUDO, M.T., RossINI, L. &STRUMIA, E. (1961) tber die Leberglykolyse von mitSchildruse gefutterten Ratten. Hoppe-Seylers Z. physiol.Chem. 326, 65.

BARKER, S.B. (1946) Effect of thyroid activity upon metabolicresponse to dinitro-ortho-cresol. Endocrinology, 39, 234.

BEAUMONT, G.E., DODDS, E.C. & ROBERTSON, J.D. (1940)Calcium and phosphorous metabolism in thyrotoxicosis.J. Endocr. 2, 237.

BERG, H. (1937) Uber den Herzmuskelstoffwechselbei Hyper-thyreose und seine Beeinflussung durch Vitamin C. Arch.exp. Path. Pharmak. 185, 359.

BING, R.J. (1961) Metabolic activity of the intact heart.Amer. J. Med. 30, 679.

BOEKELMAN, A.J. (1948) La glande thyroide. Regulatrice dupotassium. Presse med. 56, 23.

BOYD, G.S. (1959) Thyroid function, thyroxine analogs andcholesterol metabolism in rats and rabbits. Hormonesand Atherosclerosis (Ed. by G. Pincus), p. 49. AcademicPress, New York.

BREWSTER, W.R., JR, ISAACS, J.P., OSGOOD, P.F. & KING,T.L. (1956) The hemodynamic and metabolic interrela-tionships in the activity of epinephrine, norepinephrineand the thyroid hormones. Circulation, 13, 1.

BRODIE, B.B., DAVIES, J.I., HYNIE, S., KRISHNA, G. &WEISS, B. (1966) Interrelations of catechol amines withother endocrine systems. Pharmacol. Rev. 18, 273.

BROITMAN, S.A., BONDY, D.C., YACHNIN, I., HOSKINS, L.C.,INGBAR, S. & ZAMCHEK, N. (1964) Absorption and dis-position of D-xylose in thyrotoxicosis and myxedema.New Engl. J. Med. 270, 333.

BRONK, J.R. (1963) The nature of the energy requirement foramino acid incorporation by isolated mitochondria andits significance for thyroid hormone action. Proe. nat.Acad. Sci. (Wash.), 50, 524.

BRONK, J.R. (1966) Thyroid hormone: effects on electrontransport. Science, 153, 638.

BURN, J.H. & MARKS, H.P. (1925) The relation of the thyroidgland to the action of insulin. J. Physiol. (Lond.), 60, 131.

BURTON, S.D., ROBBINS, E.D. & BYERS, S.O. (1958) Utiliza-tion of glucose by hyperthyroid isolated rat liver. Proc.Soc. exp. Biol. (N. Y.), 92, 272.

B

CHANCE, B. (1965) Reaction of oxygen with the respiratorychain in cells and tissues. J. gen. Physiol. 49, 163.

CHATAGNER, F. & GAUTHERON, D. (1960) Influence deshormones thyroidiennes sur la teneur en adenosine tri-phosphate du foi du rat. Biochim. biophys. Acta, 41, 544.

CHILSON, O.P. & SACKS, J. (1959) Effect of hyperthyroidismon distribution of adenosine phosphates and glycogen inliver. Proc. Soc. exp. Biol. (N. Y.), 101, 331.

COGGESHALL, H.C. & GREENE, J.A. (1933) The influence ofdesiccated thyroid gland, thyroxin, and inorganic iodine,upon the storage of glycogen in the liver of the albino ratunder controlled conditions. Amer, J. Physiol. 105, 103.

CRISPELL, K.R., PARSON, W. & HOLLIFIELD, G. (1956) Astudy of the rate of protein synthesis before and duringthe administration of L-triiodothyronine to patients withmyxedema and healthy volunteers using N-15 glycine.J. clin. Invest. 35, 164.

DAVIDSON, I.W.F., SALTER, J.M. & BEST, C.H. (1960) Theeffect of glucagon on the metabolic rate of rats. Amer. J.clin. Nutr. 8, 540.

DAYTON, S., DAYTON, J., DRIMMER, F. & KENDALL, F.E.(1960) Rates of acetate turnover and lipid synthesis innormal, hypothyroid and hyperthyroid rats. Amer. J.Physiol. 199, 71.

DEBONS, A.F. & SCHWARTZ, I.L. (1961) Dependence of thelipoytic action of epinephrine in vitro upon thyroidhormone. J. Lipid Res. 2, 86.

DEITRICH, R.A. & SMITH, D.L. (1960) Effect of the thyroidon butyrate oxidation in the rat heart. Biochem. Pharmacol.3, 85.

DILLON, R.S. & HOCH, F.L. (1968) Iodine in mitochondriaand nuclei. Biochem. Med. (In press).

D'IORIO, A. & LEDUC, J. (1960) The influence of thyroxineon the o-methylation of catechols. Arch. Biochem. Biophys.87, 224.

Dow, D.S. (1967) The isolation from thyrotoxic and diabeticrats of skeletal muscle mitochondria showing tight coupl-ing, high respiratory indices, and normal adenosinetriphosphatase activities. Biochemistry, 6, 3350.

Dow, D.S. & ALLEN, C.E. (1961) Steady-state oxidation ofglucose in hyperthyroid and hypothyroid rats. Can. J.Biochem. Physiol. 39, 981.

DRILL, V.A. (1943) Interrelations between thyroid functionand vitamin metabolism. Physiol. Rev. 23, 355.

DRILL, V.A. & TRUANT, A.P. (1947) Effect of thyroidectomyon conversion of carotene to vitamin A. Endocrinology,40, 259.

DUTOIT, C.H. (1952) The effects of thyroxine on phosphatemetabolism. In: Phosphorus Metabolism (Ed. by W. D.McElroy and B. Glass), p. 597. The Johns Hopkins Press,Baltimore.

ELLIS, S. (1956) The metabolic effects of epinephrine andrelated amines. Pharmacol. Rev. 8, 485.

ELRICK, H., HLAD, C.J. & ARM, Y. (1961) Influence ofthyroid function on carbohydrate metabolism and a newmethod for assessing response to insulin, J. clin. Endocr.21, 387.

ERNSTER, L., IKKOS, D. & LUFT, R. (1959) Enzymic activitiesof human skeletal muscle mitochondria: a tool in clinicalmetabolic research. Nature (Lond.), 184, 1851.

ERNSTER, L. & LUFT, R. (1964) Mitochondrial respiratorycontrol: biochemical, physiological, and pathologicalaspects. Advanc. Metab. Disorders, 1, 95.

FERRINI, O., PERRONI, G.L. & BESTAGNO, M. (1959) Distri-bution of methionine-S36 in the rat. Hormonal influenceon the incorporation of amino acids into muscle protein.Minerva nucleare, 3, 210; (Chem. Abstr. 55, 18922G, 1961).

FISHER, J.N. & BALL, E.G. (1967) Studies on the metabolismof adipose tissue. XX. The effect of thyroid-status uponoxygen consumption and lipolysis. Biochemistry, 6, 637.

copyright. on M


http://pmj.bm

j.com/

Postgrad M


ay 1968. Dow

nloaded from

http://pmj.bmj.com/


FLACH, F.F., CELIAN, C.I., STOKES, P.E. & RAWSON, R.W.(1959) The influence of thyroid hormones on metabolismin psychiatric disorders. I. The effect of 3:5:3'-triiodo-thyronine on calcium and phosphorus metabolism inpsychiatric patients. J. clin. Endocr. 19, 455.

FLETCHER, K. & MYANT, N.B. (1960) Effects of thyroxineon the synthesis of cholesterol and fatty acids by cell-freefractions of rat liver. J. Physiol. (Lond.), 154, 145.

FLETCHER, K. & MYANT, N.B. (1962) Effect of thyroxine onthe synthesis of lipids in rat liver. Endocrinology, 71, 870.

FRAENKEL-CONRAT, J. & GREENBERG, D.M. (1946) Acetyla-tion of sulfanilamide as influenced by the thyroid. Proc.Soc. exp. Biol. (N. Y.), 63, 537.

FRIEDBERG, F. & GREENBERG, D.M. (1947) Endocrineregulation of amino acid levels in blood and tissues.J. biol. Chem. 168, 405.

GANJU, S.N. & LOCKETT, M.F. (1958) The action of thyroidhormones on the oxygen consumption and resistance tocold of adrenalectomized and thyroidectomized mice.J. Endocr. 16, 396.

GERSHBERG, H. & KUHL, W.J., JR. (1950) Acetylation studiesin human subjects with metabolic disorders. J. clin. Invest.29, 1625.

GERSHOFF, S.N., VITALE, J.J., ANTONOWICZ, I., NAKAMURA,M. & HELLERSTEIN, E.E. (1958) Studies of interrelation-ships of thyroxine, magnesium and vitamin B1,. J. biol.Chem. 231, 849.

GLOCK, G.E., MCLEAN, P. & WHITEHEAD, J.J. (1956) Path-ways of glucose catabolism in rat liver in alloxan diabetesand hyperthyroidism. Biochem. J. 63, 520.

GOETSCH, E. & RITZmANN, A.J., JR (1934) Thyroid disorders.VI. The suprarenal factor in reactions to thyroidectomy.Arch. Surg. 29, 492.

GOODMAN, H.M. & BRAY, G.A. (1966) Role of thyroidhormones in lipolysis. Amer. J. Physiol. 210, 1053.

GOODMAN, H.M. & KNOBIL, E. (1959) Mobilization of fattyacids by epinephrine in normal and hypophysectomizedRhesus monkeys. Proc. Soc. exp. Biol. (N. Y.), 100, 195.

HAGEN, J.H. (1960) Effect of insulin on the metabolism of adi-pose tissue from hyperthyroid rats. J. biol. Chem. 235,2600.

HANDLER, P. (1948) The influence of thyroid activity on theliver and plasma lipides of choline- and cystine-deficientrats. J. biol. Chem. 173, 295.

HARARY, I. (1958) The effect in vivo of thyroxine on acylphosphatase of rat liver and muscle. Biochim. biophys. Acta,29, 647.

HED, R., KIRSTEIN, L. & LUNDMARK, C. (1958) Thyrotoxicmyopathy. J. Neurol. Neurosurg. Psychiat. 21, 270.

HERNBERG, C.A. (1960) Bone phosphorous metabolism invitro in thyrotoxicosis. Acta endocr. (Kbh.), 33, 577.

HOCH, F.L. (1962a) Thyrotoxicosis as a disease of mito-chondria. New Engl. J. Med. 266, 446 and 498.

HOCH, F.L. (1962b) Biochemical actions ofthyroid hormones.Physiol. Rev. 42, 605.

HOCH, F.L. (1965a) Synergism between calorigenic effects:L-thyroxine and 2,4-dinitrophenol or sodium salicylate ineuthyroid rats. Endocrinology, 76, 335.

HOCH, F.L. (1965b) L-Thyroxine in subcalorigenic doses:rapid potentiation of dinitrophenol-induced calorigenesisin hypothyroid rats. Endocrinology, 77, 991.

HOCH, F.L. (1966) Rapid effects of a subcalorigenic dose ofL-thyroxine on mitochondria. J. biol. Chem. 241, 524.

HOCH, F.L. (1967) Early action of injected L-thyroxine onmitochondrial oxidative phosphorylation. Proc. nat. Acad.Sci. (Wash.), 58, 506.

HOCH, F.L. (1968a) Biochemical action of thyroid hormone.In: Proc. 3rd Midwest Conference on Thyroid, 1967.University of Missouri Press, Columbia.

HOCH, F.L. (1968b) Thyroid hormone action on mitochon-dria. I. Respiration, effects of inhibitors of respiration.Arch. Biochem. Biophys. (In press).

HOCH, F.L. (1968c) Thyroid hormone action on mitochon-dria. IX. Effects of dinitrophenol. Arch. Biochem. Biophys.(In press).

HOCH, F.L. & LIPMANN, F. (1954) The uncoupling of respira-tion and phosphorylation by thyroid hormones. Proc. nat.Acad. Sci. (Wash.), 40, 909.

HOCH, F.L. & MOTTA, M.V. (1968) Reversal of early thyroidhormone action on mitochondria by bovine serumalbumin in vitro. Proc. nat. Acad. Sci. (Wash.), 59, 118.

HUEBER, E.F. v. (1939) 1Jber die Beeinflussung von Hyper-thyreosen durch Magnesiumglutaminat. Wien. klin.Wschr. 52, 932.

JEANRENAUD, B. (1961) Dynamic aspects of adipose tissuemetabolism: a review. Metabolism, 10, 535.

JOHNSON, R.M. & BAUMANN, C.A. (1947) The effect ofthyroid on the conversion of carotene into vitamin A.J. biol. Chem. 171, 513.

JOHNSON, P.C., PosEY, A.F., PATRICK, D.R. & CAPUTTO, R.(1958) Incorporation of P,, in the muscle by normal andthyrotoxic resting rats. Amer. J. Physiol. 192, 279.

JONES, J.E., DESPER, P.C., SHANE, S.R. & FLINK, E.B. (1966)Magnesium metabolism in hyperthyroidism and hypo-thyroidism. J. clin. Invest. 45, 891.

KADENBACH, B. (1966) The influence in vivo of thyroidhormones on oxidative phosphorylation and enzymicactivities in mitochondria. Biochem. Z. 344, 49.

KARP, A. & STETTEN, D., JR. (1949) The effect of thyroidactivity on certain anabolic processes studied with the aidof deuterium. J. biol. Chem. 179, 819.

KASBEKAR, D.K., LAVATE, W.V., REGE, D.V. & SREENIVASAN,A. (1959) A study of vitamin B,, protection in experi-mental thyrotoxicosis in the rat. Biochem. 1. 72, 374.

KENDALL, E.C. (1929) Thyroxine. The Chemical CatalogueCo., New York.

KLEBANOFF, S.J. (1959) An effect of thyroxine and relatedcompounds on the oxidation of certain hydrogen donorsby the peroxidase system. J. biol. Chem. 234, 2437.

KLINGENBERG, M. (1963) Morphological and functionalaspects of pyridine nucleotide reactions in mitochondria.In: Energy-linked Functions of Mitochondria (Ed. byB. Chance), p. 121. Academic Press, New York.

KRANE, S.M., BROWNELL, G.L., STANBURY, J.B. & CORRIGAN,H. (1956) The effect of thyroid disease on calcium meta-bolism in man. J. clin. Invest. 35, 874.

KRITCHEVSKY, D. (1960) Influence of thyroid hormones andrelated compounds on cholesterol biosynthesis anddegradation: a review. Metabolism, 9, 984.

LABOUESSE, J., CHATAGNER, F. & JOLLES-BERGERET, B.(1960) Dosage du phosphate de pyridoxal dans le foie durat normal, du rat thyrotoxique et du rat thyroidectemis6.Biochim. biophys. Acta, 39, 372.

LAMBERG, B.A. (1965) Glucose metabolism in thyroiddisease. Acta med. scand. 178, 351.

LEHN1NGER, A.L. (1964) The Mitochondrion, p. 263. Benjamin,New York.

LENGEMANN, F.W., WASSERMAN, R.H. & COMAR, C.L.(1960) The effect of growth and thyroid hormones uponthe removal by lavage of calcium and strontium from theskeleton of the rat. Endocrinology, 67, 535.

LESLIE, I. & SINCLAIR, R. (1959) The action of thyroxineand triiodothyronine on human cells growing in tissueculture. Exp. Cell Res. 17, 272.

LIPSKY, S.R., BONDY, P.K., MAN, E.B. & McGUIRE, J.S., JR(1955) The effects of triiodothyronine on the biosynthesisof plasma lipids from acetate-l-C14 in myxedematoussubjects. J. clin. Invest. 34, 950.

LOEB, L. & FRIEDMAN, H. (1932) Exophthalmos produced byinjections of acid extract of anterior pituitary gland ofcattle. Proc. Soc. exp. Biol. (N. Y.), 29, 648.

copyright. on M


http://pmj.bm

j.com/

Postgrad M


ay 1968. Dow

nloaded from

http://pmj.bmj.com/

Biochemistry of hyperthyroidism and hypothyroidism 361

LooMis, W.F. & LIPMANN, F. (1948) Reversible inhibitionof the coupling between phosphorylation and oxidation.J. biol. Chem. 173, 807.

MACHO, L. (1958) The influence of endocrine glands oncarbohydrate metabolism. II. The glucose tolerance andclearance of glucose in healthy subjects and in patientswith hypo- and hyperthyroidism. Acta med. scand. 160,485.

MACHO, L. (1961) Effect of thyroxine and 2,4-dinitrophenolon the rate of utilization of glucose. Nature (Lond.), 191,604.

MAGNUs-LEVY, A. (1895) Ober den respiratorischen Gas-wechsel unter dem Einfluss der Thyroidea sowie unterverschiedenen pathologischen Zustlinden. Berl. klin.Wschr. 32, 650.

MALEY, G.F. (1957) Comparison of some enzyme systemsin normal and thyrotoxic rat livers. Amer. J. Physiol.188, 35.

MALEY, G.F. & LARDY, H.A. (1953) Metabolic effects ofthyroid hormones in vitro. II. Influence of thyroxine andtriiodothyronine on oxidative phosphorylation. J. biol.Chem. 204, 435.

MALEY, G.F. & LARDY, H.A. (1955) Efficiency of phosphor-ylation in selected oxidations by mitochondria from normaland thyrotoxic rat livers. J. biol. Chem. 215, 377.

MARTIUS, C. & HEss, B. (1952) Ober den Wirkingsmechanis-mus der Schilddrusenhormons. Arch. exp. Path. Pharmak.216, 45.

MEANS, J.H., DEGROOT, L.J. & STANBURY, J.B. (1963) TheThyroidand its Diseases, 3rd edn. McGraw-Hill, New York.

MILLIKAN, C.H. & HAINES, S.F. (1957) The thyroid gland inrelation to neuromuscular disease. Arch. intern. Med. 92, 5.

MIRSKY, I.A. & BROH-KAHN, R.H. (1936) The effect ofexperimental hyperthyroidism on carbohydrate meta-bolism. Amer. J. Physiol. 117, 6.

MUNRO, D.S., RENSCHLER, H. & WILSON, G.M. (1958)Exchangeable potassium and sodium in hyperthroidismand hypothyroidism. Metabolism, 7, 124.

NIKKILA, E.A. & PITKANEN, E. (1959) Liver enzyme patternin thyrotoxicosis. Acta endocr. (Kbh.), 31, 573.

NISHIKAWARA, M.T. & GABRIELSON, E. (1961) Hexokinaseand phosphatase activities of the intestinal mucosa inhypophysectomized and thyroid-treated hypophysecto-mized rats. Endocrinology, 68, 855.

OKUDA, K. & CHOW, B.F. (1961) The thyroid and absorptionof vitamin B,, in rats. Endocrinology, 68, 607.

PARK, J.H., MERIWETHER, B.P. & PARK, C.R. (1956) Effectsof adrenochrome on oxidative phosphorylation in livermitochondria. Fed. Proc. 15, 141.

PETER, J.B. & LEE, L.D. (1967) Characteristics of skeletalmuscle mitochondria isolated by a new improved technique.Biochem. biophys. Res. Commun. 29, 430.

PETERS, R.A. & ROSSITER, R.J. (1939) Thyroid and vitaminB,. Biochem. J. 33, 1140.

PLUMMER, H.S. & BOOTHBY, W.M. (1923) The cost of workin exophthalmic goiter. Amer. J. Physiol. 63, 406.

PORTUGAL'SKAYA, E.A. (1961) Effect of the thyroid hormoneon conversion of carotene to vitamin A in animal body.Vitaminy, Akad. Nauk. UKr. S.S.R, 4, 78 (Chem Abstr.55, 737g, 1961).

RACKER, E. (1965) Mechanisms in Bioenergetics. AcademicPress, New York.

RAWSON, R.W., RALL, J.E. & SONENBERG, M. (1955) Thechemistry and physiology of the thyroid. The Hormones,(Ed. by G. Pincus and K. V. Thimann), vol. 3, p. 433.Academic Press, New York.

RICH, C., BIERMAN, E.L. & SCHWARTZ, I.L. (1959) Plasmanonesterified fatty acids in hyperthyroid states. J. clin.Invest. 38, 275.

RIVLIN, R.S. & LANGDON, R.G. (1966) Regulation of hepaticflavine adenine dinucleotide levels by thyroid hormone.Advance Enzyme Regulation, 4, 45.

ROBERTS, K.E., FIRMAT, G., PRUNIER, J., SCHWARTZ, M.U.& RAWSON, R.W. (1956) Effect of phosphate in enhancingaction of triiodothyronine. Endocrinology, 59, 565.

ROODYN, D.B., FREEMAN, K.B. & TATA, J.R. (1965) Thestimulation by treatment in vivo with triiodothyronine ofamino acid incorporation into protein by isolated rat-livermitochondria. Biochem. J. 94, 628.

ROSENMAN, R.H., BYERS, S.O. & FRIEDMAN, M. (1952) Themechanism responsible for the altered blood cholesterolcontent in deranged thyroid states. J. clin. Endocr. 12, 1287.

Rupp, J., PASCHKIS, K.G. & CANTAROW, A. (1949) Influenceof thyroxine on protein metabolism. Endocrinology, 44,449.

SCAIFE, J.F. & MIGICOVSKY, B.B. (1957) Effect of alloxan,insulin, and thyroxine on cholesterol and fatty acidsyntheses by rat liver homogenates. Can. J. Biochem.35, 15.

SCHWARTZ, I.L. & DEBONS, A.F. (1959) Action of thyroidhormone on the release of fatty acids from tissue stores.Physiologist, 2, 104.

SELENKOW, H.A. & MARCUS, F.I. (1960) Masked hyper-thyroidism and heart disease. Med. Clin. N. Amer. 44, 1305.

SHORR, E., RICHARDSON, H.B. & WOLFF, H.G. (1933) Endo-genous glycine formation in myopathies and Graves'disease. Proc. Soc. exp. Biol. (N. Y.), 31, 207.

SOKOLOFF, L., FRANCIS, C.M. & CAMPBELL, P.L. (1964)Thyroxine stimulation of amino acid incorporation intoprotein indenendent of any action on messenger RNAsynthesis. Proc. nat. Acad. Sci. (Wash.), 52, 728.

SOKOLOFF, L. & KAUFMAN, S. (1959) Effects of thyroxine onamino acid incorporation into protein. Science, 129, 569.

SOKOLOFF, L. & KAUFMAN, S. (1961) Thyroxine stimulationof amino acid incorporation into protein. J. biol. Chem.236, 795.

SOKOLOFF, L., KAUFMAN, S., CAMPBELL, P.L., FRANCIS, C.M.& GELBOIN, H.V. (1963) Thyroxine stimulation of aminoacid incorporation into protein. Localization of stimulatedstep. J. biol. Chem. 238, 1432.

STERNHEIMER, R. (1939) The effect of a single injection ofthyroxine on carbohydrates, protein and growth in therat liver. Endocrinology, 25, 899.

STOCKER, W.W., SAMAHA, F.J. & DEGROOT, L.J. (1966)Coupled oxidative phosphorylation in muscle of thyro-toxic patients. Program of the 23rd Annual Meeting,Amer. Fed. Clin. Res., May 1966. J. clin. Invest. 45, viii.

TABACHNICK, I.I.A. & BONNYCASTLE, D.D. (1954) The effectof thyroxine on the coenzyme A content of some tissues.J. biol. Chem. 207, 757.

TAPLEY, D.F. (1955) Magnesium balance in myxedematouspatients treated with triiodothyronine: preliminary note.Bull. Johns Hopk. Hosp. 96, 274.

TAPLEY, D.F. & COOPER, C. (1956) Effect of thyroxine onthe swelling of mitochondria isolated from varioustissues of the rat. Nature (Lond.), 178, 1119.

TATA, J.R. (1963) Inhibition of the biological action ofthyroid hormones by actinomycin D and puromycin.Nature (Lond.), 197, 1167.

TATA, J.R. (1967) The formation and distribution of ribo-somes during hormone-induced growth and development.Biochem. J. 104, 1.

TATA, J.R., ERNSTER, L., LINDBERG, E., ARRHENIUS, E.,PEDERSEN, S. & HEDMAN, R. (1963) Action of thyroidhormones at the cell level. Biochem. J. 86, 408.

TATA, J.R. & WIDNELL, C.C. (1966) Ribonucleic acidsynthesis during the early action of thyroid hormones.Biochem. J. 98, 604.

THORN, G.W. (1936) Creatine studies in thyroid disorders.Endocrinology, 20, 628.

THORN, G.W. & EDER, H.A. (1946) Studies on chronicthyrotoxic myopathy. Amer. J. Med. 1, 583.

copyright. on M


http://pmj.bm

j.com/

Postgrad M


ay 1968. Dow

nloaded from

http://pmj.bmj.com/


WAINFAN, E. & MARX, W. (1955) Effects of thyroxine andsome related compounds on bacterial oxidations. J. biol.Chem. 214, 441.

WANG, E. (1946) Creatine metabolism and endocrine regula-tion. Acta med. scand. Suppl. 169, 1.

WAYNE, E.J. (1960) Clinical and metabolic studies in thyroiddisease. Brit. med. J. i, 1; 78.

WEISS, W.P. & SOKOLOFF, L. (1963) Reversal of thyroxine-induced hypermetabolism by puromycin. Science, 140,1324.

WERTHEIMER, E. & BENTOR, V. (1953) Metabolic changesin the rat diaphragm during heat regulation as a thyroxineeffect. Metabolism, 2, 536.

WHITE, J.E. & ENGEL, F.L. (1958) Lipolytic action ofcorticotropin on rat adipose tissue in vitro. J. clin. Invest.37, 1556.

WIDNELL, C.C. & TATA, J.R. (1963) Stimulation of nuclearRNA polymerase during the latent period of action ofthyroid hormones. Biochim. biophys. Acta, 72, 506.

WILKINs, L. & FLEISCHMANN, W. (1946) Effects of thyroid oncreatine metabolism with a discussion of the mechanismof storage and excretion of creatine bodies. J. clint. Invest.25, 360.

WILLIAMS, R.H., EGANA, E., ROBINSON, P., AsPER, S.P. &DuToIT, C. (1943) Alterations in biologic oxidation inthyrotoxicosis. I. Thiamine metabolism. Arch intern. Med.72, 353.

WISWELL, J.G. (1961) Some effects of magnesium loading inpatients with thyroid disorders. J. clin. Endocr. 21, 31.

WOHL, M.G. & FELDMAN, J.B. (1939) Vitamin A deficiencyin disease of the thyroid gland: Its detection by darkadaptation. Endocrinology, 24, 389.

WOHL, M.G., LEVY, H.A., SZUTrKA, A. & MALDIA, G.(1960) Pyridoxine deficiency in hyperthyroidism. Proc.Soc. exp. Biol. (N. Y.), 105, 523.

ZILE, M. & LARDY, H.A. (1959) Monoamine oxidase activityin liver of thyroid-fed rats. Arch. Biochem. Biophys. 82, 411.

copyright. on M


http://pmj.bm

j.com/

Postgrad M


ay 1968. Dow

nloaded from

http://pmj.bmj.com/

biochemistry of hyperthyroidism and hypothyroidism* · rna-metabolism and the earlier changes in...

Documents