Postgraduate Medical Journal (May 1973) 49, 355-358.

CASE REPORTS

Hypogammaglobulinaemia with Whipple's disease

M. COCHRAN*M.B., Ch.B., M.R.C.P.

J. C. GALLAGHERM.B., Ch.B., M.R.C.P.

M. G. COOKM.B., Ch.B.

University Department of Surgery

M. PEACOCKM.B., Ch.B., M.R.C.P.

Medical Research Council Mineral Metabolism Unit, The General Infirmary, Leeds

SummaryThe patient, a 54-year-old housewife, was well untilthe age of 40 years when she developed repeatedinfections. During the next 10 years recurrent attacksof diarrhoea also appeared and were associated withweight loss, increased skin pigmentation, and later theoccurrence of arthralgia and polyserositis. She wasfound to have deficiencies of IgG and IgA. A mal-absorption syndrome was established and shown to bedue to Whipple's disease by jejunal biopsy. She alsohad hypocalcaemia and osteomalacia. Weekly injec-tions of human gammaglobulin had no effect on eitherthe diarrhoea or the arthralgia, although the severityof respiratory infections was reduced. Intramuscularinjections of vitamin D failed to restore the serumcalcium to normal. Continuous oral tetracycline wasfollowed by marked symptomatic improvement, dis-appearance of the diarrhoea and some weight gain.Steatorrhoea however persisted and the jejunal histo-logy showed only slight improvement. The serumcalcium returned to normal possibly as a result ofcorrection of a magnesium deficiency. The relevanceof the hypogammaglobulinaemia to the Whipple'sdisease is discussed, and a search of the literatureshows six other cases where both disorders wereassociated.

HYPOGAMMAGLOBULINAEMIAcomprisesanuncommongroup of disorders which usually occur in infancybut may appear at any age (Hobbs, 1970). The clinicalsyndrome depends on the results of the immuno-logical defect and associated non-immunologicalfeatures. In the patient reported here, increasinglysevere infections over a 10-year period led to thediagnosis, and a malabsorption syndrome whichappeared during this time was shown to be due toWhipple's disease. Since this condition is extremelyrare in females, its occurrence with another un-common disorder made it seem probable that the two

* Present address: Renal Unit, Royal Hospital, Sheffield.

were in some way linked. It is generally agreed thatWhipple's disease is infective in origin, and it issuggested that the infection in this case was theresult of the hypogammaglobulinaemia. A numberof previously reported patients with Whipple'sdisease also had proved or possible immunologicaldeficiencies.

Case reportThe patient, a 54-year-old housewife, was com-

pletely well until 1956 when she began to complainof recurrent attacks of malaise, pyrexia and rigors.In 1963 she was admitted to hospital with lobarpneumonia and there were three similar episodesduring the next 4 years.

In 1963 she developed episodes ofwatery diarrhoeausually followed by acute bronchitis or pleurisy, andher weight fell from 50 to 32 kg. She noted thattetracycline given for the bronchitis was invariablyfollowed by remission of the diarrhoea. In 1966 shedeveloped pain and morning stiffness of the knees,wrists and metacarpo-phalangeal joints with a dorsalsheath effusion and the appearance of small nodulesat the elbow. In 1967 a diagnosis of hypogamma-globulinaemia was made by plasma electrophoresisand from that time the patient has been given weeklyintramuscular injections of 6 ml of human gamma-globulin (HGG). She has had no further pneumoniabut the arthralgia has persisted.

She was admitted for assessment of a probablemalabsorption syndrome in 1969.On examination she was a thin, pigmented woman

weighing 36 kg. There was no lymphadenopathy butthe spleen was palpable 2 cm below the costal margin.Investigations showed plasma albumin 4-4 g/100 ml,globulin 1-3 g/100 ml; quantitative immunoglobulins:IgG, 115 mg/100 ml; IgA 10 mg/100 ml; IgM 270mg/100 ml. Plasma cells were absent on sternalmarrow examination which also showed depletediron stores. A hypochromic anaemia was present

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(Hb 8-8 g/100 ml, serum iron 40 t/g/100 ml). Serumfolate and B12 were in the normal range, with thepatient on folate supplements. Faecal fat was 96 gin 5 days and only 10% of an oral xylose load wasexcreted in 5 hr. A jejunal biopsy was reported asshowing non-specific villous atrophy. The serumcalcium was 7-0 mg/100 ml; magnesium 1-5 mg/100 ml; phosphate 3-3 mg/100 ml; alkaline phos-phatase 14 KA units. A calcium balance showed anaverage negative balance of 4-6 mg/kg body weight/day, and a very low urinary calcium excretion of15 mg/24 hr. Total urinary hydroxyproline excretionwas 64 mg/24 hr. An iliac crest biopsy showed mildosteomalacia. There was no radiological evidence ofjoint disease and the Rose-Waaler test was negativeon four occasions. At that time a diagnosis of hypo-gammaglobulinaemia with associated malabsorptionand arthritis was made. A gluten-free diet was of nobenefit over a 6-month period. There was noreticulocytosis after intramuscular iron and theserum calcium remained low in spite of weeklyinjections of vitamin D2 100,000 units.

In 1971 an influenza-like illness was followed byacute pericarditis, which remitted without the use ofantibiotics. Later in the same year the patient wasadmitted during an exacerbation of diarrhoea.On examination, she was weak, dehydrated and

had a grossly distended abdomen. Initial investiga-tions showed severe hypocalcaemia and dilated loopsof small bowel. Electrolyte correction and oral tetra-cycline 250 mg q.d.s. led to rapid improvement inher condition. She was re-investigated with resultsessentially unchanged since 1969, and the immuno-globulins were IgG, 130 mg/100 ml; IgA, 8 mg/100 ml; IgM, 430 mg/100 ml. The diagnosis ofWhipple's disease was made from a second jejunalbiopsy.The patient was given continuous oral tetracycline

and reassessed 4 months later. The intramuscularvitamin D and HGG were unaltered. There was nofurther diarrhoea and she felt considerably moreenergetic, and had gained 6 kg in weight. A 5-dayfaecal fat, however, was 65 g. Another jejunal biopsywas taken for light and electron microscopy. Anormocytic anaemia (Hb 9-5 g/100 ml) was presentand the marrow contained excess iron stores. Theserum calcium had risen to 10-0 mg/100 ml, theserum magnesium was 2-1 mg/100 ml and thealkaline phosphatase 8 KA units. A second iliaccrest biopsy was normal, showing active mineraliza-tion. The nodules near the elbow were examinedhistologically and showed fibrinoid necrosis withpatchy vascular infiltration of lymphocytes, con-sistent with a rheumatoid nodule.

Jejunal biopsy microscopy. The biopsies obtainedwith a Crosby capsule were examined initially innormal saline by dissecting microscopy and unusual

nodular clubbed villi without leaf forms of ridgingwere noted.The diagnosis of Whipple's disease was made from

the histological appearances of the second biopsy inJanuary 1971, which showed characteristic plumpgranular macrophages staining intensely withperiodic acid-Schiff(Fig. 1). These findings prompteda review of the histology of the biopsy taken in 1969.The same features as in the second specimen werethen seen. These features comprised crypt hyper-plasia with partial villous atrophy. In the laminapropria there were slightly dilated lymphatics andindistinct lipid-filled spaces with adjacent eosinophiland neutrophil polymorphs. The Gram stain showedpossible micro-organisms lying free in the laminapropria. The macrophages contained only faintgranules when stained for iron and the presence ofmuciphages and amyloid material was excluded(Hourihane, 1963, 1966). No plasma cells weredemonstrated in the lamina propria. The thirdbiopsy, taken after 4 months tetracycline therapy,was examined by electron microscopy and intra- andextracellular rod-shaped bacteria were shown to bepresent in the lamina propria (Figs. 2 and 3). Theepithelium appeared normal but abundant lipid waspresent in extracellular globular collections withinvilli, and within some macrophages (Figs. 2 and 4).Numerous macrophages contained lysosomes dis-tended by membrane-like material (Fig. 4) whichwas presumed to be derived from ingested bacteria(Hendrix & Yardley, 1970).Discussion

In this patient a dysgammaglobulinaemia appearedat the age of 40, with recurrent infections. It wascharacterized by very low IgG and IgA with raisedIgM levels, corresponding to Type 2 dysgamma-globulinaemia in the terminology of West, Hong &

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FIG. 1. The tip of a jejunal villus containing in the laminapropria numerous large histiocytes with granular cyto-plasm (PAS x180).

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Case reports 357

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FIG. 2. A bacilliform organism B is present in the laminapropria among abundant extracellular globular lipid G(electron micrograph x 32,000). H is a histiocyte.

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Holland (1962). Subsequently she developed theclinical picture of Whipple's disease with a mal-absorption syndrome and progressive wastingaccompanied by arthralgia and polyserositis. How-ever, the diagnosis of Whipple's disease was notmade until examination of jejunal tissue showedcharacteristic changes, emphasizing the point madeby Hendrix & Yardley (1970) that the pathologistshould be prepared to suspect this condition fromroutine histological preparations.The pathogenesis of Whipple's disease is obscure

but has been fully discussed by Hendrix & Yardley(1970) and by Maizel, Ruffin & Dobbins (1970). It ishowever, agreed that invasion of the gut with small

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FIG. 4. Some intra-cellular lipid I is present in a histiocytewith dilated lysosomes L containing presumed bacterialremnants (electron micrograph x 13,200).

Gram-positive bacilli is the first step and a failure oflysis of the membranes of the micro-organisms bymacrophages leads to the PAS-staining granulesformed within these cells. The actual organismresponsible has not been identified but it seems likelythat man has a high resistance to it, accounting forthe low prevalence ofthe disease, of which only about150 cases have been described. In our patient, theinfection was almost certainly the result of theimmunological defect, and this might also be trueof other cases of Whipple's disease. A paucity ofplasma cells in the lamina propria is a feature ofuntreated Whipple's disease (Dobbins & Ruffin,1967) and examination of the published series showsthat a number of cases had immunological defici-encies of some kind (Table 1). Furthermore, there isa well established association between malabsorptionand hypogammaglobulinaemia (Conn & Quintiliani,1966) and Whipple's disease was not excluded in allof the reported cases.

In our patient, tetracycline always brought abouta remission of the diarrhoea, but even after 4 months'

TABLE 1. Immunological defects in previously reportedcases of Whipple's disease

Authors Date Defect

Sandor & Kozmer 1957 HypogammaglobulinaemiaMartel & Hodges 1959 Casel: Hypogamma-

globulinaemiaAnton 1961 HypogammaglobulinaemiaMaxwell et al. 1968 Impaired lymphocyte activityBerens, Cohen &Sichwabe 1969 IgM deficiency

Mazel et al. 1970 IgA deficiency

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continuous therapy steatorrhoea persisted and therewas no definite improvement in the histologicallesions in the jejunal mucosa. There are many casesreported where there has been rapid clearing of theorganisms with antibiotic therapy, and the in-complete success in this case may have been due tothe co-existing hypogammaglobulinaemia. Strober,Blaese & Waldmann (1970) have shown that IgA isonly transferred from serum to mucosal surfaces inminimal quantities, so that intramuscular administra-tion of HGG, which furthermore contains littleIgA, would be unlikely to protect the patient fromgastro-intestinal infections. Nonetheless, the patientappears to benefit from the therapy in that severerespiratory infections have been prevented.The hypocalaemia was not corrected by large

doses of parenteral vitamin D2 given over 18 months,but shortly after tetracycline was begun the serumcalcium rose to normal levels for the first time. Thismay have resulted from the spontaneous correctionof a magnesium deficiency (Heaton & Fourman,1965) since the serum magnesium had risen tonormal levels (Fig. 5). The second bone biopsyshowed active mineralization in contrast to theprevious specimen. The anaemia did not respond tohaematinics, but refractory anaemias are a feature ofmany inflammatory processes including Whipple'sdisease.

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FIG. 5. Serum calcium and magnesium changes withtherapy.

The relation ofthe arthralgia to the other symptomsis not clear. The joint pain and stiffness of hands,wrists and knees with minimal swelling and anabsence of erosions is completely consistent withWhipple's syndrome. However, the fibrinoid necrosis

in the biopsied nodules supports the alternativediagnosis of rheumatoid arthritis. Joint disease in-distinguishable from rheumatoid arthritis with anegative Rose-Waaler test has been described withhypogammaglobulinaemia (Bywater & Ansell, 1969),but the arthritis of Whipple's disease is also sero-negative.

AcknowledgmentsWe wish to thank Professor B. E. C. Nordin and Professor

M. Losowsky for their help in the management of this case,and Dr R. Whitehead with whom the histology was discussed.We are also grateful to Mr T. Watson of the Leeds Uni-

versity Department of Cancer Research for his technicalassistance in the electron microscopy and to Mrs SusanBaguley for the histological preparations.

ReferencesANTON, A.T. (1961) Agammaglobulinaemia complicating

Whipple's disease: Case report. Ohio Medical Journal, 57,650.

BERENS, S.C., COHEN, R.A. & SCHWABE, A.D. (1969) Diag-nostic problems of partially treated Whipple's disease:Report of a case with isolated deficiency of immuno-globulin M. California Medicine, 110, 477.

BYWATERS, E.G.L. & ANSELL, B. (1969) The rarer arthriticsyndromes. In: Textbook of Rheumatic Diseases (Ed. byW. S. C. Copeman), 4th edn, p. 535. Livingstone, London.

CONN, H.O. & QUINTILIANI, R. (1966) Severe diarrhoeacontrolled by gammaglobulin in a patient with agamma-globulinaemia, amyloidosis and thymoma. Annals ofInternal Medicine, 65, 528.

DOBBINS, W.O. & RUFFIN, J.M. (1947) A light and electron-microscopic study of bacterial invasion in Whipple'sdisease. American Journal of Pathology, 51, 225.

HEATON, F.W. & FOURMAN, P. (1965) Magnesium deficiencyand hypocalcaemia in intestinal malabsorption. Lancet, ii,50.

HENDRIX, T.R. & YARDLEY, J.H. (1970) Whipple's disease.In: Modern Trends in Gastroenterology (Ed. by W. I.Card and B. Creamer), p. 229. Butterworths, London.

HOBBS, J.R. (1970) Immunoglobulins in some diseases.British Journal of Hospital Medicine, 3, 669.

HOURIHANE, D.O'B. (1963) The histology of intestinalbiopsies. Proceedings of the Royal Society of Medicine,56, 1073.

HOURIHANE, D.O'B. (1966) The pathology of malabsorptionstates. In: Recent Advances in Pathology (Ed. by C. V.Harrison), 8th edn, p. 321. Churchill, London.

MAIZEL, H., RUFFIN, J.M. & DOBBINS, W.O. (1970) Whipple'sdisease: a review of nineteen patients from one hospitaland a review of the literature since 1950. Medicine, 49,175.

MARTEL, W. & HODGES, F.J. (1959) The small intestine inWhipple's disease. American Journal of Roentgenology, 81,623.

MAXWELL, J.D., FERGUSON, A., MCKAY, A.M., IMRIE, R.C.& WATSON, W.C. (1968) Lymphocytes in Whipple'sdisease. Lancet, i, 887.

SANDOR, T. & KOZMER, J. (1957) (Budapest) (August)Magyar Belrosi Archirum, 98.

STROBER, W., BLAESE, R.M. & WALDMANN, T.A. (1970) Theorigin of salivary IgA. Journal of Laboratory and ClinicalMedicine, 75, 856.

WEST, C.D., HONG, R. & HOLLAND, N.H. (1962) Immuno-globulin levels from the newborn period to adulthood inimmunoglobulin deficiency states. Journal of ClinicalInvestigation, 41, 2054.

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