igg s gamma globulin) metabolism hypogammaglob- ulinemia...

Journal of Clinical InvsatigationVol. 44, No. 9, 1965

IgG (7 S GammaGlobulin) Metabolism in Hypogammaglob-ulinemia: Studies in Patients with Defective Gamma

Globulin Synthesis, Gastrointestinal Protein Loss,or Both *

THOMASA. WALDMANNt ANDPAULJ. SCHWAB(From the Metabolism Service, National Cancer Institute, Bethesda, Md. 20014)

The factors that control the rates of gammaglobulin synthesis and catabolism and thus regu-late the body pool of gammaglobulin are not wellunderstood. Although antigenic stimulation is amajor factor regulating the synthesis of immuno-globulins by plasma cells (1-3), other factors suchas the metabolic rate (4) and the serum concentra-tion of gamma globulin (5-11) modify gammaglobulin metabolism.

The availability of patients with hypogamma-globulinemia presents an opportunity to investi-gate the role played by the serum gammaglobulinconcentration in the regulation of gammaglobulinsynthesis and catabolism in man. Hypogamma-globulinemia may be secondary to a defect ingamma globulin synthesis, to excessive gammaglobulin catabolism, or to urinary or gastrointesti-nal loss of this protein. The defect in gammaglobulin synthesis is in some cases a congenitalhereditary disorder limited largely to males,whereas in other patients it is an acquired defectin gamma globulin synthesis, usually idiopathic,but occasionally secondary to neoplasms includingmultiple myeloma, chronic lymphocytic leukemia,and thymoma (12).

The survival of gammaglobulin has been stud-ied in patients with defective gammaglobulin syn-thesis and extreme hypogammaglobulinemia bydetermining the rate of decline of the serumgamma globulin concentration after the infu-sion of exogenous normal gammaglobulin. In 16of the 17 patients studied by this technique (12-18), the gammaglobulin survival tj ranged from30 to 70 days. In one patient studied by Seltzer,

* Submitted for publication March 3, 1965; acceptedMay 27, 1965.

t Address requests for reprints to Dr. Thomas A.Waldmann, Metabolism Service, National Cancer Insti-tute, Bethesda, Md. 20014.

Baron, and Toporek (15), the survival tj was 12days. No normal subjects could be studied bythis technique, since such subjects have a highendogenous serum gammaglobulin concentration.The survival of gamma globulin in normal sub-jects has, however, been studied with I'31-gammaglobulin. The tj of survival in these studiesranged from 17 to 32 days (9, 19), suggesting thatthe survival of gammaglobulin was prolonged inpatients with hypogammaglobulinemia due to de-fective synthesis. In accord with this conclusion,Solomon, Waldmann, and Fahey (9) and Ander-sen (20) found that the survival of gammaglobu-lin was prolonged in some patients with a re-duced concentration of this protein, secondaryto chronic lymphocytic leukemia, multiple mye-loma, or macroglobulinemia. However, Lang,Schettler, and Wildhack (21), Owen, McKenzie,and Huizenga (22), and Koblet, Digglemann,Barandun, and Kaser (23) found a comparablesurvival of IP8l-gamma globulin in control sub-jects and patients with hypogammaglobulinemia.Bronsky, Dubin, and Kushner (18) using sulfur""-labeled amino acids found short gamma globulinsurvivals of 5, 8, and 25 days compared to albu-min survivals of over 40 days in agammaglobu-linemic patients.

Holman, Nickel, and Sleisenger (24) andAndersen (20) found that the survival of gammaglobulin was short in patients with excessive gas-trointestinal albumin loss (exudative enteropathy).In the present study, the metabolism of I'll-labelednormal albumin and gammaglobulin was investi-gated in 14 control subjects, 7 patients with exu-dative enteropathy, and 9 patients with hypogam-maglobulinemia due to defective synthesis. Thetotal body protein pools as well as the rates of al-bumin and gammaglobulin synthesis and catabo-lism were measured.

1523

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IGG (7 S GAMMAGLOBULIN) METABOLISMIN HYPOGAMMAGLOBULINEMIA

MethodsPatients studied. IgG (7 S gamma globulin) metabo-

lism was studied in two categories of patients with hy-pogammaglobulinemia, those with defective synthesis andthose with excessive protein loss. The latter group in-cluded seven patients with excessive gastrointestinal pro-tein loss, marked hypoalbuminemia, moderate edema, andslight diarrhea. The diagnosis of excessive gastroin-testinal protein loss was established with I'-albuminand Cr'-albumin (25) (Table I). Each of the patientshad a marked increase in the fractional catabolic rateof I'-albumin and excessive fecal excretion of Cr' af-ter intravenous administration of Cr'-albumin. Thesubjects included one patient with regional enteritis, onewith chronic pancreatitis and severe malabsorption, andone patient with a generalized myopathy with associatedcardiomegaly, congestive heart failure, and secondary in-testinal protein loss similar to that previously describedwith constrictive pericarditis (26). One patient hadgastrointestinal protein loss, anemia, eosinophilia, andgrowth retardation, apparently secondary to gastroin-testinal allergy (27). Three patients had intestinallymphangiectasia, a syndrome in which gastrointestinalprotein loss is associated with lymphocytopenia, dilatedlymphatic channels of the small bowel, and generalizedlymphatic disorders (24, 28).

Nine patients with hypogammaglobulinemia (agamma-globulinemia) due to defective production were studied.This group included three patients with congenital hypo-gammaglobulinemia of the sex-linked recessive type andsix subjects with idiopathic acquired hypogammaglobu-linemia. Two of the patients, one with congenital hypo-gammaglobulinemia and one with idiopathic acquired hy-pogammaglobulinemia, had associated gastrointestinaldisorders. The patient with congenital hypogammaglobu-linemia had ileocolitis; the patient with acquired hypo-gammaglobulinemia had a chronic Salmonella newportinfection and a sprue-like syndrome with diarrhea andsteatorrhea. These two patients were shown to have as-sociated gastrointestinal protein loss by I'-albumin andI`-polyvinylpyrrolidone (PVP) (29) and are consid-ered separately from the other seven patients with agam-maglobulinemia.

Fourteen normal adults ranging in age from 21 to 45served as controls for the I'-albumin and I'-gammaglobulin studies. Normal values for the Cr'-albumin andIP-PVP tests were determined in 60 and 10 subjects,respectively, with diseases not affecting the gastrointesti-nal tract.

All patients were hospitalized during the 4- to 6-weekperiod of the turnover study. Each of the patients hadan adequate diet with an intake of over 1,500 calories.None of the patients was febrile or had proteinuria. Liverfunction tests, including alkaline phosphatase, serumbilirubin, serum glutamic-pyruvate transaminase, andcephalin flocculation, were normal in each of the sub-jects. None of the patients were taking medications.

Preparation and labeling of normal gamma globulin(IgG) for turnover studies. Gamma globulin for la-

beling was prepared by curtain electrophoresis from nor-mal serum with a model B Beckman curtain electropho-resis apparatus. After an 8-hour period of equilibrationof the curtain apparatus with a 0.033 M pH 8.6 barbitalbuffer, a sample of normal serum diluted 2: 1 with thebarbital buffer was applied to the curtain at a rate of0.5 to 1 ml per hour. The separation was performed witha current of 35 ma, 700 v for 24 hours. The effluent wascollected in a series of 32 tubes, and the protein concen-trations of the samples were estimated from their opticaldensity at a wavelength of 280 mju. The tubes containingthe initial protein peak (gamma globulin) were pooledand concentrated by ultrafiltration. Cohn Fraction V(Red Cross albumin) was used to prepare the I-albumin.

The gamma globulin and albumin preparations wereiodinated with reducing agent-free Na-IP by the iodinemonochloride method of McFarlane (30). The final prod-uct contained from 0.3 to 1 mole of iodine per mole ofprotein. Over 99% of the final products were precipitablewith 10%o phosphotungstic acid. The iodinated proteinwas passed through a 0.22-,u Millipore filter, and 70 mgof sterile human albumin was added per ml to preventdamage due to self-radiation. All radioactivity in the I-gammaglobulin preparations migrated as a gammaglobu-lin on paper electrophoresis. On passage of the iodinatedgamma globulin over DEAE-cellulose according to themethod described by Fahey and Horbett (31), over 98%of the radioactivity was found in the area of the peak ofthe IgG molecules with no label in the gamma macro-globulin (IgM) area.

Experimental protocol. Each patient received 0.5 ml ofLugol's solution every 8 hours throughout the period ofstudy to inhibit thyroidal uptake of I' released by thebreakdown of the labeled protein. Approximately 100 ,cof I'-protein was administered intravenously from acalibrated syringe to each patient. Blood samples wereobtained without stasis from the patients at 15- and 30-minute intervals, after administration of the iodinatedprotein, and then three to five times a week for the next20 days, and placed in bottles with EDTAanticoagulant.Urine and feces were collected in 24-hour lots throughoutthe entire study. The samples were assayed for radio-activity with appropriate standards in a gamma ray well-type scintillation counter with a thallium-activated so-dium iodide crystal.

The total serum proteins were determined by a biuretmethod. The serum samples were analyzed weeklythroughout the study period by paper eletcrophoresis witha pH 8.6 barbital buffer to determine the serum albuminand gammaglobulin concentrations (32). The IgG con-centration was also estimated by the quantitative immuneprecipitin method described by Fahey and McKelvey (33).There was no significant change in the serum gammaglobulin or albumin concentrations during the study inany of the patients.

The I'-protein turnover data were analyzed accord-ing to a modification of the metabolic clearance tech-nique described by Berson, Yalow, Schreiber, and Post(34), and Pearson, Veall, and Vetter (35). The follow-

1525


ing equations summarize the calculations: Plasma vol-ume (PV) = administered radioactivity/radioactivity permilliliter of plasma at zero time (extrapolated from 15-and 30-minute values). Total circulating IgG = PVXserum IgG concentration. Radioactivity retained in body=activity administered minus cumulative radioactivity inurine and stool. Fraction of body IgG intravascular =(PV X plasma radioactivity per milliliter) /radioactivityretained in body (this fraction is determined after com-pletion of equilibration of I'-IgG among the body com-partments after days 6 to 8). Total body IgG pool=total circulating IgG/fraction of body IgG intravascular.Fraction of circulating IgG catabolized per day= radio-activity excreted in urine and stools per 24-hour period/mean circulating radioactivity during the same period.This fraction was determined for each collection period,and the mean value for the days 3 to 20 was used in thefollowing calculation: IgG turnover = total circulatingIgG X fraction of circulating IgG catabolized per day.Since the concentration of the serum proteins remainedconstant throughout the study period, the patients werefelt to be in the steady state, and the rate of gammaglobulin synthesis is considered equal to the value forgammaglobulin turnover.

Demonstration of gastrointestinal protein loss. I'3-PVP or Cr'-albumin was used to demonstrate gastro-intestinal protein loss according to methods previouslydescribed (25, 29). The patients received 25 to 35 /Acof the labeled macromolecule intravenously from a cali-brated syringe. The stools passed during the subsequent4 days were collected as a single lot in a 1-gallon stain-less steel can, brought to a constant volume, and homo-genized by agitation on a shaker. The homogenized sam-

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ples were counted with an appropriate standard on agamma ray scintillation counter. The results are ex-pressed as a percentage of the dose of administered iso-tope excreted in the 4-day feces collection.

Results

Data obtained in the I131-gamma globulin (IgG)turnover studies are recorded in Table I. Con-trol subjects had a total circulating IgG pool of0.42 to 0.72 g per kg and a total body IgG poolof 0.89 to 1.63 g per kg. From 5.6 to 8.4%o of theplasma pool of IgG was catabolized per day, cor-responding to a tj of survival derived from the se-rum curves of 18.9 to 24.1 days. From 0.024 to0.050 g per kg of IgG was turned over (synthe-sized) each day.

Patients with excessive gastrointestinal proteinloss. The serum IgG concentration and total cir-culating and total body pools of IgG were reducedin six of the seven patients. The fractional cata-bolic rate was markedly elevated for both I'31-albu-min and I'31-IgG for each of these patients. Thefractional catabolic rates for albumin and IgGwere comparable for a given patient. The rate ofIgG synthesis was slightly reduced in the patientwith pancreatitis and malabsorption, was normalor slightly increased in five patients, and was

IgG TURNOVER(SYNTHETIC RATE)

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PROTEIN LOSING AGAN6ANLUBULINENIA AGANNAGLUUULINtMIA.CASTROENTEROPATHY WITH ASSOCIATED

PROTEIN LOSINGGASTROENTEROPATHY

FIG. 1. THE IGG CATABOLIC AND SYNTHETIC RATES IN PATIENTS WITH GASTROINTESTINALPROTEIN LOSS, AGAMMAGLOBULINEMIA,AND COMBINEDDISORDERS. The range of normal valuesfor 14 subjects is indicated by the crosshatched areas.

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FIG. 2. THE SURVIVAL OF I-GAMMA GLOBULIN ANDALBUMIN IN PATIENT 14 WITH AGAMMA-

GLOBULINEMIA DEMONSTRATINGA PROLONGEDGAMMAGLOBULIN SURVIVAL AND NORMALALBUMIN

SURVIVAL.

markedly increased to three times normal in thepatient with regional enteritis.

Hypogammaglobulinemia due to defective syn-

thesis (agammaglobulinemia). Each of the ninepatients with agammaglobulinemia had a reducedserum concentration of IgG and had markedly re-

duced total circulating and total body IgG pools.The IgG synthetic rate was from 2 to 20%o ofnormal in these nine patients. In the patientswithout associated gastrointestinal protein loss, thefractional catabolic rate of IgG was below the nor-

mal range in six of the seven patients with a mean

of 4.0%o of the intravascular pool catabolized per

day (Table I, Figures 1 and 2). The mean tj ofsurvival of IgG derived from the serum curves was

38 days with a range of 28 to 71 days. The frac-tional catabolic rate for 1131-albumin was normalin the five patients studied.

The fractional catabolic rate of both I"'-IgGand I'81-albumin was increased in the two patientswith hyposynthetic hypogammaglobulinemia andassociated gastrointestinal protein loss.

Discussion

Gammaglobulin metabolism in patients withgastrointestinal protein loss. Six of the seven pa-

tients with gastrointestinal protein loss in thepresent study had decreased serum albumin andgamma globulin concentrations, markedly in-creased fractional catabolic rates of both albuminand gamma globulin, and normal or slightly in-creased gamma globulin synthetic rates. Hypo-gammaglobulinemia has been commonly associatedwith hypoalbuminemia in patients with excessiveenteric protein loss (20, 24, 28). All 45 of thepatients with excessive gastrointestinal proteinloss secondary to intestinal lymphangiectasia, gas-

trointestinal allergy, constrictive pericarditis, gas-tric rugal hypertrophy, nontropical sprue, andWhipple's disease seen at the National Institutesof Health have had a serum gammaglobulin con-

centration below 0.7 g per 100 ml. In contrast,the nine patients with regional enteritis and ul-cerative colitis and gastrointestinal protein loss had

serum gammaglobulin concentrations from 0.8 to1.7 g per 100 ml. In general, loss of proteins from

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I INALBUMIN I131 IgG I131 IgM

FIG. 3. THE FRACTIONAL CATABOLIC RATES OF ALBUMIN, IGG (7 S GAMMAGLOBU-

LIN), AND IGM (GAMMAMACROGLOBULIN)IN FOURPATIENTS WITH GASTROINTESTI-

NAL PROTEIN LOSS. The range of normal values is indicated by the crosshatchedareas.

the body should be considered when there is a

reduction in the serum concentration of both albu-min and gamma globulin, proteins formed in dif-ferent tissue sites. The possibility of gastrointesti-nal protein loss should be investigated in all pa-

tients with hypoalbuminemia and hypogamma-globulinemia where loss of these proteins is notsecondary to proteinuria, plasmapheresis, or exu-

dative dermatitis. Although the majority of suchpatients with idiopathic hypoalbuminemia and hy-pogammaglobulinemia will have significant gastro-intestinal protein loss, a similar protein patternmay be occasionally observed in patients with neo-

plastic diseases involving the lymphocytes or

plasma cells or in patients with congenital or idio-pathic acquired hypogammaglobulinemia and sec-

ondary liver disease, malnutrition, or active in-flammatory disease (36).

The fractional catabolic rates for both albuminand gamma globulin were markedly increased ineach of the seven patients with exudative enter-opathy in agreement with the findings of Holmanand associates (24) and Andersen (20), sug-

gesting that substantial quantities of gammaglobu-lin are lost into the intestinal tract in this syn-

drome. In the present study the increase in thefractional catabolic rate over normal was quitecomparable for albumin, IgG, and gammamacro-

globulin (IgM) (mol wt 1,000,000) for a givenpatient with exudative enteropathy (Figure 3).1These findings suggest that in these patients, theproteins studied were not lost selectively into theintestinal tract on the basis of size but that therewas bulk loss of plasma itself or of material witha comparable protein composition. The findingthat plasma proteins of different sizes are lost intothe intestinal tract at similar rates in exudativeenteropathy contrasts with the urinary proteinloss in the nephrotic syndrome, where the smallerserum proteins are lost preferentially and themacroglobulins are lost into the urine only whenthere is extreme renal damage (38, 39).

The role of gammaglobulin concentration in the1 The I"-gamma macroglobulin turnover studies on

these patients have been reported previously (37).

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1528


control of gammaglobulin synthesis. In the pres-ent study the synthetic rate of IgG was normal orslightly elevated in six of the seven patients withexudative enteropathy and was markedly elevatedonly in the patient with regional enteritis. Therethus appears to be little compensatory increase inthe synthesis of JgG in response to loss of thisprotein. Similarly, there was little or no increasein the rate of synthesis of IgG in patients with hy-pogammaglobulinemia and nephrosis (40) or ofgamma,-macroglobulin (IgM) in patients withgastrointestinal protein loss and associated re-duced IgM levels (37). The capacity for gammaglobulin synthesis far exceeds that seen in thesepatients with excessive gastrointestinal proteinloss, since patients with malaria have been shownto have up to five times the normal gammaglobu-lin synthetic rate (6). Thus it appears that therate of synthesis of the immune globulins is notsignificantly controlled by their serum concentra-tion or pool size, but can be accelerated by otherfactors such as antigenic exposure.

Gammaglobulin metabolism in agammaglobu-linemia. In each of the patients with agamma-globulinemia in the present study, the primary dis-order was a defect in gamma globulin synthesis.The synthesis of gammaglobulin was reduced to2 to 20%o of the normal level. In contrast to thepatients with hypogammaglobulinemia secondaryto excessive gastrointestinal protein loss, these pa-tients with nonproductive hypogammaglobuline-mia had a markedly reduced ability to synthesizespecific antibodies in response to antigenic chal-lenge, had negligible isohemagglutinin titers, andhad a decrease or absence of plasma cells (39).Many of the patients with defective gammaglobu-lin synthesis have recurrent infections and associ-ated chronic sinusitis, bronchitis, bronchiectasis,arthritis, and in 15 to 40%o of the cases unex-plained gastrointestinal tract disorders resemblingsprue or ileocolitis (36, 41). Two of the ninepatients with defective gammaglobulin synthesis,in the present study, had associated gastrointestinaldisorders with associated loss of proteins into theintestinal tract. After therapy of the patient withileocolitis with prednisolone and of the patient witha sprue-like syndrome and Salmonella newportinfection with a glutin-free diet and antibiotics,there was a return to normal serum albumin con-centration and survival but persistent extreme hy-

pogammaglobulinemia. We felt that the primarydisorder in these two patients was a defect ingamma globulin synthesis but that there was asecondary disorder of the intestinal mucosa withconsequent general enteric loss of serum proteins.The presence of secondary gastrointestinal pro-tein loss in patients with deficient production ofantibodies has been previously observed (24, 36,42) and may be a possible explanation for theoccasional short gamma globulin survivals previ-ously reported in some patients with agamma-globulinemia.

The remaining seven patients with agamma-globulinemia in the present study had a signifi-cantly reduced I'31-IgG fractional catabolic rate.The five patients in this group studied with JI3l-albumin had a normal fractional catabolic rate foralbumin. A parallel situation has been seen in apatient with analbuminemia where there was amarkedly reduced fractional catabolic rate for al-bumin and a normal fractional catabolic rate forIgG (43). Thus the survival of albumin and IgGmay vary independently of each other, suggestingthat at least part of the catabolism of these pro-teins is by pathways unique for the given proteinand that nonspecific factors, such as the bulk lossof serum into the intestinal tract postulated byothers (44, 45), are not normally the major orsole mechanism of catabolism of these serumproteins.

The pathogenesis of the decreased fractionalcatabolic rate of IgG in agammaglobulinemic pa-tients. The decreased fractional catabolic rate ofI31-IgG seen in the agammaglobulinemic patientswithout secondary enteric protein loss might beexplained by 1) an altered distribution of the IgGwith a decreased percentage of the body pool inthe catabolic site (i.e., the plasma pool or a pool inrapid equilibrium with it), 2) a defect in the cata-bolic pathways for this protein accompanying thedefect in synthesis, or 3) a manifestation of a basicpattern of IgG metabolism in which the fractionalcatabolic rate of IgG is directly correlated with andcontrolled by the serum concentration or total bodypool of IgG. In line with the possibility of al-tered distribution of the gamma globulin accom-panying changes in gammaglobulin concentration,Andersen and Bjzrneboe (46) found a markeddifference from normal in the distribution of thisprotein between the intravascular pools and ex-

1529


travascular pools in hyperimmunized rabbits.They felt that although there was a marked re-duction in the half-time of survival of gammaglobulin in hyperimmunized rabbits compared tonormal rabbits, there was a comparable fractionof the intravascular pool catabolized in bothgroups. In our study, however, and those re-ported by others, there was no difference in thedistribution of IgG between the intra- and extra-vascular pools between normal patients and ani-mals and those with agammaglobulinemia or withhypergammaglobulinemia due to hyperimmuniza-tion or multiple myeloma (7, 9, 47).

The second hypothesis is that the reduced frac-tional catabolic rate of IgG seen in these pa-tients with agammaglobulinemia may represent adefect in the catabolic pathways for this proteinassociated with the defect in synthesis. Such adisorder occurs in some patients with analbumine-mia. In analbuminemic patients there was amarked prolongation of albumin survival as wellas an almost complete defect in albumin synthesis(43, 48-50). In two of the three patients withanalbuminemia infused with sufficient albumin toreturn the albumin pool to normal, the albuminsurvival remained markedly prolonged (43, 49),but in the third patient the survival of albuminreturned to normal levels (50). There is, how-ever, no direct evidence of a defect in gammaglob-ulin catabolism in patients with agammaglobu-linemia.

There is considerable evidence that is in ac-cord with the third hypothesis, which postulatesa direct relationship between the fractional cata-bolic rate of IgG and the serum concentration ofthis protein. In accord with this hypothesis, thefractional catabolic rate of IgG was decreased inthe subjects of the present study with hyposyn-thetic hypogammaglobulinemia, as well as in sub-jects previously reported with a reduction in IgGconcentration secondary to decreased synthesis as-sociated with chronic lymphocytic leukemia, mul-tiple myeloma, or macroglobulinemia (9, 20).The fractional catabolic rate of IgG was increasedin most subjects with an elevated IgG concentra-tion associated with chronic infection (6), liverdisease (5), or multiple myeloma (7-9). A simi-lar correlation between fractional catabolic rateand serum gammaglobulin concentration has beennoted in the mouse, where there was a reduction in

the fractional catabolic rate of gammaglobulin ingerm free hypogammaglobulinemic animals (51)and an increase in the fractional catabolic rate inanimals that were hyperimmunized or had gammaglobulin-producing tumors (52). It has beenshown by Fahey and Robinson (10) and Sell (11)that the fractional catabolic rate of I'31-IgG in miceis specifically related to the concentration of IgGand not secondary to other factors such as the rateof gamma globulin synthesis or the number ofplasma cells. In their studies the fractional cata-bolic rate of IgG was significantly increased inmice infused with IgG from a number of animalsources but not in those animals infused with albu-min or gammamacroglobulin (IgM). The basicmechanism resulting in the direct correlation ofIgG and its fractional catabolic rate has not beenelucidated. There may be induction of specificcatabolic enzymes with an increase in the concen-tration of IgG. Alternatively, there may normallybe a saturable system protecting IgG moleculesfrom catabolism. As the concentration of IgG in-creases, a lower fraction of the total number ofIgG molecules would be protected by this saturablesystem, and the survival of IgG would be reduced.Just such a saturable protection system in the formof specific IgG receptors on the walls of pino-cytotic vacuoles has been suggested not only as themechanism for the correlation of IgG survival andconcentration but also as the mechanism for thespecific transport of IgG across the placenta andacross the small intestinal mucosa of many speciesof newborn animals (53).

The correlation between serum concentrationand fractional catabolic rate has so far been notedonly with IgG and perhaps albumin, and the sur-vival of a number of other serum proteins ap-pears to be independent of their serum concentra-tion or total body pool size. Gamma1-macroglobu-lin (IgM) survival has been shown to be essen-tially the same in normal controls as in patientswith markedly reduced IgM levels in agamma-globulinemia or markedly increased levels in mac-roglobulinemia of Waldenstr6m (37). Similarly,the survivals of fibrinogen (54), ceruloplasmin(55), and 82A-globulin (IgA) (56) have beenshown to be independent of the serum concentra-tion of these proteins.

Although the data in the present study are inaccord with the hypothesis that there is a corre-

1530


lation between the fractional catabolic rate ofgammaglobulin and the serum concentration, fur-ther work is dearly necessary to determine themechanism involved.

Summary

The metabolism of gammaglobulin (IgG) wasstudied in seven patients with gastrointestinal pro-tein loss, nine patients with agammaglobulinemia,and 14 control subjects. There was a reduction inthe serum concentration and total body pool size ofIgG in six of the seven patients with gastrointesti-nal protein loss studied. The fractional catabolicrate for IgG was markedly increased in each ofthese patients. In general, the increase in the frac-tional catabolic rate over normal was quite com-parable for albumin, IgG, and gamma macro-globulin (IgM) for a given patient, suggestingthat there was bulk loss of plasma or material witha comparable protein composition into the intesti-nal tract. The IgG synthetic rate was normal, orslightly increased, in six of the patients and mark-edly increased in only the one patient with regionalenteritis. This suggests that a reduced serum IgGconcentration is not a potent stimulus for IgG syn-thesis and that other factors, such as exposure toantigens, are the major stimuli to IgG production.The primary disorder in the patients with agam-maglobulinemia was a defect in gamma globulinsynthesis. Two of the nine patients developed as-sociated gastrointestinal disorders with secondarygastrointestinal protein loss and short IgG andalbumin survivals. Six of the seven remainingpatients with agammaglobulinemia had a reducedfractional catabolic rate of IgG with a normalfractional catabolic rate of albumin. The patho-genesis of this reduced fractional catabolic rateof IgG in patients with agammaglobulinemia isdiscussed.

AcknowledgmentsThe authors wish to thank Mr. William Briner of the

Radiopharmacy Service, Clinical Center, National In-stitutes of Health, for assistance in labeling the proteinpreparations and to acknowledge the many helpful dis-cussions with Dr. John L. Fahey, Immunology Branch,National Cancer Institute.

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