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Home , Fatigue, Malaise

Case in Point A 37-Year-Old Man With Symptoms of , , and Dizziness

Ifeoma S. Izuchukwu, MD, MPH; and Mary White, MD

This case reviews the presentation, workup, management, and clinical course of a patient with renal amyloid associated amyloidosis resulting in nephrotic syndrome.

common abnormal test re- to , which required transfusion. (probably renal related due to the loss sult in adults in any primary The patient refused admission but of the total binding globulin in his care practice is proteinuria, then returned with worsening symp- urine, as he became euthyroid later in A whose cause can range from toms. His chief concern was the course of the ). the benign to the more serious. Uri- and dizziness lasting 15 to 20 minutes, He had allergies to gatifloxacin, nary protein excretion of more than which was alleviated by rest. His dizzy infliximab (chosen based on case 3 g per 24 hours is likely a result of spells were sporadic but more frequent reports of anti-tumor necrosis fac- a glomerular disease and defines the on awakening. On review of his sys- tor (TNF) therapies being effective nephrotic syndrome when associ- tems, the patient described an unin- with hidradenitis suppurativa), and ated with , edema, tentional of about 5 to 6 . His current hyperlipidemia, and lipiduria. Glo- pounds per week, with a 40-pound included alendronate, calcium with merulonephropathy has a myriad of loss over the last 2 years, attributed to D, simvastatin, , causes, among which amyloidosis is an ongoing loss of appetite. hydrochlorothiazide (HCT), gaba­ considered a secondary cause. We The patient had no , vi- pentin, morphine, and topical anes- report a case of nephrotic syndrome sual disturbances, tinnitus, , or thetics. His past surgical history was caused by amyloid associated (AA) . He had no shortness of notable for surgeries for multiple ab- amyloidosis, which we suspected was breath, , sputum, and hemop- scesses (right axilla, groin, scrotum, due to chronic systemic tysis. He also had no chest , pal- and posterior neck) and an aortic- from hidradenitis suppurativa. pitations, and claudication, but he did valve replacement surgery following notice swelling of his legs. He did not infectious endocarditis secondary to CASE PRESENTATION have abdominal pain, melenic stools, line sepsis—this admission was for a A 37-year-old man with a history of and hematemesis. He also did not hidradenitis suppurativa flare and the hidradenitis suppurativa was seen in have any lower urinary tract symp- peripherally inserted central catheter the emergency room (ER) for symp- toms, but he did notice foamy urine. (PICC line) was for intravenous anti- toms of worsening fatigue, mal- He did not have , polypha- biotics. Unfortunately, records of this aise, and dizziness that persisted for gia, and heat or cold intolerance. He admission showed no echocardio- 1 week. The patient had been to the also noted generalized xerosis with gram report, although the physicians ER 1 week prior for fatigue secondary small amounts of drainage from his reported it was done. right axilla, lower back, neck, and The patient lived with his wife and

Dr. Izuchukwu is an attending physician in the groin lesions. sons and did not smoke or drink al- Department of Ambulatory Care and Dr. White The patient did not have any mus- cohol. He said he never used illicit is transitional care director in the Department of culoskeletal concerns. In addition substances. His family history was Transitional Care Medicine, both at the VA Greater Los Angeles Healthcare System in Los Angeles, to hidradenitis suppurativa, his past significant for a 30-year-old brother California. Dr. Izuchukwu and Dr. White are both medical history was significant for who died of renal-cell carcinoma. associate health sciences professors in the De- sickle cell trait (SCT) and beta thal- partment of Medicine at the David Geffen School of Medicine at the University of California in Los assemia, , hyperlipid- INITIAL EXAM Angeles, California. emia, and subclinical The patient’s temperature was 98.6°F,

MARCH 2012 • FEDERAL PRACTITIONER • 19 CASE IN POINT

Table 1. Laboratory tests cant for an increased absolute neutro- Test name Result Reference range phil count of 207,000 uL. His urinalysis revealed a proteinuria range of 300 to Transferrin 140 mg/dL 180­-329 mg/dL 600 mg/dL but bland sediment on mi- TIBCa calculatorb 188 mcg/dL 240-­400 mcg/dL croscopy without evidence of . Plain radiograph of the chest was Ferritin 121.5 ng/mL 22-­322 ng/mL normal with no pulmonary infiltrates or effusions and post sternotomy changes Hb F 0.0% 0.0­-2.0% with aortic valve replacement noted. Hb S 31.4% 0.0­-0.0% The patient was admitted for treatment of acute renal failure and anemia. Hb C 0.0% 0.0­-0.0% DIAGNOSIS AND TREATMENT Hb A 64.6% 94­-98% Over the course of the patient’s 3-day Hb A2 4.0% 1.5­-3.0% hospitalization, he received a trans- fusion of 2 units of packed red blood Hb solution Positive Negative cells, which increased his Hb to 8.1 g/dL. The laboratory workup of his c QIG-IgA 412 mg/dL 82­-453 mg/dL anemia revealed a mixed anemia con- QIG-IgM 93.6 mg/dL 46­-304 mg/dL sistent with chronic disease, iron de- ficiency, SCT, and beta QIG-IgG 1,150 mg/dL 751­-1,560 mg/dL (Table 1). Previous outpatient workup for proteinuria revealed a 24-hour QIG-κ 924 mg/dL 629­-1,350 mg/dL proteinuria of 5.9 g/day with hypoal- QIG-λ 530 mg/dL 313­-723 mg/dL buminemia and an elevated low-den- sity lipoprotein cholesterol. A 2.5 g aTIBC: Total iron-binding capacity; bEvaluation: TIBC calculator = Transferrin x 1.34; cQIG: Quantita- increase of 24-hour urine protein was tive immunoglobulin. observed within a 2-week period. A pulse 71 beats per minute, blood pres- out clubbing or cyanosis. Pulses were partial immunologic workup was then sure 124/73 mm Hg, respirations 19 strong bilaterally. His skin had multi- conducted and completed at his ad- breaths per minute, and oxygen satu- ple areas of scarring and fibrosis of the mission. During his hospitalization, ration 98% on room air. He was well- posterior neck, bilateral axillae, peri- his serum creatinine increased from groomed, in no apparent distress, and anal, perineal, and buttock regions. 2 mg/dL to 4 mg/dL, with continuing well nourished. He was alert and fully Laboratory data revealed an increase proteinuria, and the nephrology ser- oriented. His head was normocephalic, in serum creatinine from baseline of vice was consulted. atraumatic, pupils equally round and 0.8 mg/dL to 1 mg/dL to 2.4 mg/dL and A common approach to the dif- reactive to light, extraocular muscles an increase in blood urea nitrogen from ferential diagnosis of nephrotic syn- were intact, conjunctivae were pale, baseline of 6 mg/dL to 10 mg/dL to drome is to identify whether the sclera anicteric, and the oropharynx 44 mg/dL. The complete blood count nephrotic syndrome may be due to a was nonerythematous. His chest had a was significant for hemoglobin (Hb) of primary or secondary cause (Table 2). healed sternotomy scar. 6.9 g/dL and hematocrit of 21.8%, with In adults, systemic such as The cardiovascular examination baseline indexes of 9 g/dL and 28%, re- , systemic erythemato- was unremarkable with a jugular ve- spectively. The mean corpuscular vol- sus, and amyloidosis can account for nous pressure estimated to be 6 cm. ume was 60.6 fL and mean corpuscular almost 30% of nephrotic syndrome The lungs were clear to auscultation Hb was 19.4 pg. His platelets were at cases. Primary renal disorders make bilaterally. The abdomen was rotund 478,000. His white blood cell (WBC) up the remaining cases with minimal with striae, soft and nontender, with- count had been chronically elevated change disease, focal segmental glo- out evidence of organomegaly. Bowel and on presentation was 21.7 K/uL, merulosclerosis, and membranous sounds were normal. He had bilateral which was at his baseline value WBC. nephropathy leading the group. Inter- lower extremity pitting edema with- The differential diagnosis was signifi- estingly, published reports cite mem-

20 • FEDERAL PRACTITIONER • MARCH 2012 CASE IN POINT

Table 2. Differential diagnosis of branous nephropathy, followed by centrations may guide nephrotic syndrome minimal change disease, as the most empiric anti-inflamma- common malignancy-associated glo- tory treatment in similar Primary merulonephropathy, occurring with patients.4 • Minimal change disease many carcinomas and occasionally Colchicine has be- • Focal segmental glomerulosclerosis 1 with and . come the accepted • Membranous nephropathy therapy for secondary • Membranoproliferative glomerulonephritis Pathological Diagnosis amyloidosis, particularly A transjugular needle biopsy of the in cases due to famil- • Rapidly progressive glomerulonephritis was performed to determine ial Mediterranean fever. • Congenital/genetic syndromes the cause of the proteinuria. Unfor- Newer agents that spe- -Denys-Drash syndrome, Frasier tunately, there was not sufficient tis- cifically interfere with syndrome, familial focal segmental sue to evaluate for glomerular disease. fibril formation are still glomerulosclerosis, Galloway-Mowat However, tissue from the cortico-med- under development.5 syndrome, oculocerebrorenal syndrome ullary junction stained with Congo Administration of im- Secondary red was diagnostic of AA amyloidosis. munosuppressive and • cytostatic drugs can be - B, hepatitis C TREATMENT AND OUTCOME initiated only after the -HIV/AIDS This 37-year-old man had nephrotic evaluation of the renal -, , CMV, rubella, syndrome due to secondary amyloi- histology and determina- toxoplasmosis dosis. Treatment of nephrotic syn- tion of overall risk status drome can be divided into general of the patient. Steroids, • Drugs and specific modalities.2 General treat- used as immunosup- -Nonsteroidal anti-inflammatory drugs ments aim to reduce proteinuria and pressives, can be sup- (NSAIDs) lessen peripheral edema. It is gener- plemented with other -Interferon ally necessary to administer angioten- cytostatic treatments. - sin-converting-enzyme inhibitors or New therapies, such as -Gold, mercury, angiotensin receptor blockers to con- mycophenolate mofetil -Penicillamine trol the proteinuria, and a loop or rituximab, can be -Pamidronate is usually required to treat the periph- used in resistant cases. • Systemic illnesses eral edema. The associated hyperlipid- Our patient was - emia typically resolves or reverses with treated symptomatic­ally -Vasculitides: Wegner’s granulomatosis, resolution of the nephrotic syndrome. with fluid restriction, ir- Churg-Strauss syndrome, polyarteritis Initiation of anticoagulant treatment besartan, a low-salt diet, nodosa, Henoch-Schönlein purpura, may be necessary as these patients and HCT. He also re- systemic have a higher incidence of thrombo- ceived a blood transfu- -Malignancies: carcinoma, lymphoma, embolic events. sion. However, he opted leukemia Specific control of the underlying to leave the hospital in -Immune complex deposition: IgA inflammatory process, giving rise to 3 days and follow up as nephropathy, postinfectious glomerulone- the amyloid, ideally helps control the an outpatient to specialty phritis (later stage), primary amyloidosis, nephrotic syndrome. Renal amyloido- clinics. secondary amyloidosis sis, which is rapidly progressive and Adapted from Seldin DC, Skinner M. Amyloidosis. In: Fauci AS, associated with a poor prognosis, has DISCUSSION Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal no standardized therapy. Prognos- Secondary AA amyloi- Medicine. 17th ed. New York, NY: McGraw-Hill Companies, Inc; tic factors in amyloidosis include the dosis is a systemic dis- 2008:chap 28. quantity of amyloid deposition in the order caused by tissue kidney and the extent of glomerular, deposition of fibrils composed of SAA matic or chronic inflammatory condi- tubulointerstitial, and vascular dam- protein fragments. The SAA protein is tions (eg, chronic infections). Unlike age.3 Frequent measurements of the an acute phase reactant whose levels light chain amyloidosis (AL), AA am- serum amyloid A (SAA) protein con- may be persistently elevated in rheu- yloidosis has become a less prevalent

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disease entity due to the reduced inci- can thus be considered as the deter- tial conflicts of interest with regard to dence of diseases such as , mining histological factor for predict- this article. osteomyelitis, or bronchiectasis in the ing clinical manifestations and final Western Hemisphere.6 outcome of renal AA amyloidosis.8 Disclaimer In one study, renal involvement In our patient, despite the multi- The opinions expressed herein are those represented by nephrotic syndrome tude of infections over time, includ- of the authors and do not necessarily and renal failure were observed in ing treatment-related adverse effects, reflect those of Federal Practitioner, 59% and 54% of cases, respectively.6 the original reason for these infections Quadrant HealthCom Inc., the U.S. The presence of lambda light chains, were hidradenitis suppurativa flare- Government, or any of its agencies. either in serum or urine, is associ- ups, and we dare to postulate that This article may discuss unlabeled or ated with higher levels of protein- hidradenitis suppurativa caused the investigational use of certain drugs. uria and reduced renal function. The AA amyloidosis. Hidradenitis suppu- Please review complete prescribing in- distribution pattern of glomerular rativa is the only recurrent infection formation for specific drugs or drug amyloid deposits and the glomerular for all the years of patient care and combinations—including indications, inflammatory reaction are indepen- hospitalizations. A similar case report contraindications, warnings, and ad- dent factors influencing proteinuria by Titze et al recounted a male of the verse effects—before administering level. Tubular and the abun- same age at presentation who had the pharmacologic therapy to patients. dance and distribution pattern of glo- same fistulization in both axillary, in- merular amyloid deposits at the time guinal, and perineal area, cardiac in- REFERENCES of biopsy are independent predictors volvement, and multiple surgeries.9 1. Gupta K, Nada R, Das A, Kumar MS. Membrano­ proliferative glomerulonephritis in a carcinoma with of renal outcome. He was treated for secondary infec- unknown primary: An autopsy study. Indian J Pathol Since patients with AA amyloido- tions with intravenous antibiotics. Microbol. 2008;51(2):230-233. 2. Gero L. Treatment of nephrotic syndrome in the sis show decreased renal function at He also developed progressive kid- adult. Orv Hetil. 2006;147(48):2313-2318. presentation relative to patients with ney disease and nephrotic syndrome 3. Sasatomi Y, Sato H, Chiba Y, et al. Prognostic factors for renal amyloidosis: A clinicopathological study AL amyloidosis, patients with chronic treated in the same manner as our using cluster analysis. Intern Med. 2007;46(5):213-219. inflammatory disorders should be case (ramipril, triamterene, and HCT). 4. Gillmore JD, Lovat LB, Persey MR, Pepys MB, routinely evaluated for amyloidosis.6 The major difference from our case is Hawkins PN. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating con- Despite the possible significant la- a strong family history of hidradenitis centration of serum amyloid A protein. Lancet. tency between the onset of inflamma- suppurativa, which, according to our 2001;358(9275):24-29. 5. Gorevic PD. Treatment of secondary (AA) amy- tion and clinical presentation with AA patient, was not part of his family his- loidosis. UpToDate. 19.3 Web site. http://www amyloidosis, amyloid progression can tory. The other concomitant diagnosis .uptodate.com/contents/treatment-of-secondary -aa-amyloidosis?source=search_result&search=trea be rapid, thus a timely diagnostic tis- in our patient of SCT was beta thal- tment+of+aa+amyloidosis&selectedTitle=1%7E57. sue biopsy should be pursued. assemia, which has no documented Updated February 2, 2011. Accessed March 20, 2011. 6. Bergesio F, Ciciani AM, Santostefano M, et al; Immu- The factors associated with a poor relationship with nephrotic syndrome. nopathology Group, Italian Society of Nephrology. prognosis include older age, a reduced A PubMed review did not reveal any Renal involvement in systemic amyloidosis—­An Italian retrospective study on epidemiological and serum albumin concentration, preex- correlation as of this writing. Ac- clinical data at diagnosis. Nephrol Dial Transplant. isting renal dysfunction at baseline, cording to the case series report, the 2007;22(6):1608-1618. 7. Lachmann HJ, Goodman HJ, Gilbertson JA, et al. and the degree of SAA elevation dur- optimal method for diagnosis of AA Natural history and outcome in systemic AA amyloi- ing follow-up. Increased production amyloidosis remains controversial.10 l dosis. N Engl J Med. 2007;356(23):2361-2371. 8. Verine J, Mourad N, Desseaux K, et al. Clinical and of SAA was the most powerful risk histological characteristics of renal AA amyloidosis: factor for end-stage renal failure and Acknowledgement A retrospective study of 68 cases with a special inter- est to amyloid-associated inflammatory response. death but was also one that could be The authors wish to thank Talene Chur- Hum Pathol. 2007;38(12):1798-1809. ameliorated through anti-inflamma- ukian, MD, and Mark Horng, MD, for 9. Titze J, Schneider M, Krause H, et al. Diarrhea, nephrotic syndrome and hidradenitis suppu- tory treatment; in one study, stabiliza- their contributions to this paper. rativa: An unusual case. Nephrol Dial Transplant. tion or regression of amyloid deposits 2003;18(1):192-194. 10. Gertz MA, Kyle RA. Secondary systemic amyloido- and prolonged survival were inversely Author disclosures sis: Response and survival in 64 patients. Medicine related.3,7 Glomerular involvement The authors report no actual or poten- (Baltimore). 1991;70(4):246–256.

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