Case presentation HH. Reza Malekzadeh

Transcription

1 Case presentation HH Reza Malekzadeh

2 Classification of Iron Overload and Hemochromatosis (HC) Primary Hereditary HC 1-HFE associate (Type1) C282Y Homozygosity C282Y/H63D Hetrozygosity 2-Non HFE-associated Hereditary HC Secondary Acquired HC 1-Iron loading anemia (thalassemias.) 2-Diatary overload 3-Multiple transfusions Others:Hemodialysis,HCV,Nash,

3 Acquired Causes of Iron Overload Acquired iron overload Iron-loading anemias Thalassemia major Sideroblastic anemia Chronic hemolytic anemia Dietary iron overload Chronic liver diseases ØHepatitis C ØAlcoholic liver disease ØNAFLD Bacon BR, et al. Gastroenterology 1999; 116:193

4 Iron Overload In chronic Liver Disease Chronic liver diseases commonly associated with Iron overload: Hepatitis C Alcoholic liver disease NAFLD Chronic liver diseases rarely associated with Iron overload: AIH HBV Cryptogenic cirrhosis

5 Causes of the elevated transferrin saturation in the absence of HH High serum iron levels due to hepatic cytolysis (sever viral, alcohol, Non Alcoholic or AI hepatitis) Low transferrin levels due to liver failure have been ruled

6 Case presentation 22 y/o female with epigastric colicky pain referred to RUQ & LUQ from 4 months ago found to has Icter, hyperpigmentation skin,lower extremity edema,amenorrhea from 2 months ago,loss of appetite,weight loss,intermittent fever and chills,increased urine color & clay feces. PE: Jaundice,LEE,Splenomegaly,mild to moderate ascites

7 Sonography&ENDOSCOPY Small & atrophic, hyper echo live with course parenchyma, nodular margin, distended GB, ascites and splenomegaly. 2 rows of grade 1 varices, mild PHG with petechial lesion in antrum & fundus

8 Lab AST: 734 ALT: 640 ALP: 380 LDH: 158 Bili T: 6.1 Bili D: 2.5 Hb: 11 MCV: 104 Ferritin: 1590 (14-165) IRON: 294 (35-155) TIBC: 318 ( ) SI: 92.1 % ANA: +VE CRP: +VE HBsAg: _VE HCV Ab: _VE

9 WBC: 100 PMN: 75% RBC: 70 Alb: 0.7 Serum protein: 8 Serum Alb: 2.6 SAAG: 1.9 LAB (Ascites) HIGH SAAG ASCITES

10 GAMM:

11 LAB. AMA: 1/80 ( _VE) ASMA: 1/80 (<1/80) LKM1 Ab: _Ve 24 hrs urine volume 600 ( )ml/day 24hrs urine cooper <10 (15-50)mcg/day 24hrs urine Cr 1284 ( )mg/day Serum ceruloplasmin 38 ( )mg/dl Serum Cu 88 (70-140)mcg/dl Genetic Study:H63 D Heterozygote

12 Chronic hepatitis. Grade=13 Stage=3

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14 LAB.2 months after after steroid therapy WBC; Hb:14 MCV:100 Plt: FBS: 71 Urea: 22 Cr: 0.6 Fe:120(41-132) TIBC: 300( ) Ferritin:59(10-90) AST:44 ALT: 46 ALP: 95 CRP: -VE ESR: 8 Bili: 1.85 Bili D:0.5

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16 LAB AST=34 Alt=120 Ferretin=350,Fe=140 TIBC=250.GGT=88,Ceruloplasmin=35 Viral and AI marker =negative Hb=14,HB electerophoresis=nl Platelate=240000

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21 Comparative Overview of the Primary Iron-Overload Disorders Classified as Hereditary Hemochromatosis Reza Malekzadeh DDRC/TUMS

22 Simplified classification of hereditary iron overload Reza Malekzadeh DDRC/TUMS

23 Characteristic of HH -I Type of HH Gene product Known or postulated function(s) I-HFE HFE Interaction with TfR1 for uptake of Fe. Modulation of Hepcidin expression. II-Juvenile HJV Hemojuvelin? Modulation of Hepcidin expression III-Juvenile HAMP Hepcidin Decrease Fe release from enterocytes, macrophage.. Iv-TfR2 Transferrin receptor 2 Increase uptake of Fe by Hepatocytes V-Ferroportin Ferroportin Export of Fe from enterocytes, macrophage & Hepatocytes

24 Characteristic of HH-2 Type of HH Decade of age at presentation Potential for organ damage FE Predominant in: Main organ involved I-HFE 4 th or 5th Variable Parenchyma Liver,Heart, Endocrine glands II-Juvenile HJV III-Juvenile HAMP 2 nd or 3rd High Parenchyma 2 nd or 3rd High Parenchyma Iv-TfR2 4 th or 5th Variable Parenchyma V-Ferroportin 4 th or 5th low Reticuloendothelial system Liver,spleen

25 Characteristic of HH-3 Type of HH Treatment HB Inheritance Response to phlebatomy I-HFE Phlebotomy Autosomal recessive II-Juvenile HJV Phlebotomy Normal Autosomal recessive Excellent Excellent III-Juvenile HAMP Phlebotomy Normal Autosomal recessive Excellent Iv-TfR2 Phlebotomy Normal Autosomal recessive Excellent V-Ferroportin?Chelation May be low Autosomal Dominant Fair

26 Juvenile-onset phenotype The juvenile-onset phenotype is much more severe. Plasma iron loading and tissue iron excesses (reflected by increased transferrin-saturation values and serum ferritin levels, respectively) are evident early in life in both sexes. Reza Malekzadeh DDRC/TUMS

27 Adult onset Hereditary Hemochromatosis, 1-Mutations in the transferrin receptor 2 gene ( TfR2) appears to be very similar to that of classic, HFE -related hemochromatosis 2-HFE -related hemochromatosis Both charcterize by gradual iron loading, a relatively late onset of parenchymal iron deposition, an predominantly hepatic organ damage. 3- Hereditary Ferroportin disease :Quit different from HFE HH Reza Malekzadeh DDRC/TUMS

28 Types of juvenile-onset HH 1-Mutation in the HAMP gene, which encodes hepcidin, a peptide that plays a key role in human iron metabolism. 2-Mutation in hemojuvelin(hjv) gene that originally called HFE2. Reza Malekzadeh DDRC/TUMS

29 Ferroportin: Iron Exporter Control iron release from hepatocytes and, importantly, macrophages Ferroportin is inhibited directly by hepcidin, a key iron-regulatory peptide Reza Malekzadeh DDRC/TUMS

30 Ferroportin The only known mammalian iron exporter, The protein is expressed on macrophages from which it mediates release of iron for use in distant tissues. Hepcidin, binds ferroportin precipitating its internalization and lysosomal degradation. The interplay between hepcidin and ferroportin is thus a vital mechanism for controlling iron export from macrophages and maintaining body iron balance.

31 Ferroportin disease (HH type 4) Single missense mutations in the Ferroportin (SLC40A1) gene are associated with iron overload syndromes inherited as an autosomal dominant trait. An increasingly recognized cause of hepatic iron overload in patients with hyperferritinemia; Reza Malekzadeh DDRC/TUMS

32 Hereditary Ferroportin disease have been classified into two principal groups 1- Macrophage type (M-type) : with low transferrin saturation have what has been termed ferroportin disease, associated with loss-of function mutations and consequent iron trapping in macrophages. 2- Hepatic- type :with high transferrin saturation and hepatocellular iron overload. (p.n144h and p.c326y mutations).either partial (p.n144h) or complete (p.c326y) resistance to the inhibitory effect of hepcidin Reza Malekzadeh DDRC/TUMS

33 Types of Ferroportin HH Patients with macrophage type (M-type) ferroportin disease, have loss-of function mutations and consequent iron trapping in macrophages clinically have low transferrin saturation Patients with hepatocellular iron overload (Htype) has high transferrin saturation Either have partial (p.n144h) or complete (p.c326y) resistance to the inhibitory effect of hepcidin with Fe trapping into hepatocytes.

34 Raised serum ferritin with normal or low transferrin saturation In contrast to HFE-related hemochromatosis, individuals with SLC40A1 mutations typically have raised serum ferritin concentrations with normal or low transferrin saturation and excess iron storage, predominantly in macrophages. Reza Malekzadeh DDRC/TUMS

35 Not restricted to Caucasians The disorder is typified by a raised ferritin with normal or low transferrin saturation and a tendency for anaemia with poor venesection tolerance. Not restricted to Caucasians, the condition is recognized in Asians and a unique and common polymorphism (Q248H) in southern African populations may contribute to the iron overload observed. Reza Malekzadeh DDRC/TUMS

36 Iron loading occurs predominantly within the RES Iron loading occurs predominantly within the reticuloendothelial system with splenic uptake visible on magnetic resonance imaging; in the liver Kupffer cells become iron-laden with relative sparing of hepatocytes The Ferroportin mutation locks iron within macrophages and it has been suggested that the reduced availability of plasma iron to bind transferrin drives increased intestinal absorption Reza Malekzadeh DDRC/TUMS

37 Reza Malekzadeh DDRC/TUMS

38 Normal liver has the same intensity as spleen and muscle Reza Malekzadeh DDRC/TUMS

39 Iron overload occurs in the liver only in HFE-related haemochromatosis Reza Malekzadeh DDRC/TUMS

40 Low signal intensity on T2- weighted magnetic resonance imaging confirms iron deposition in both liver and spleen of a patient with Ferroportin mutation Reza Malekzadeh DDRC/TUMS

41 Case 3 presentation A 64 yr old male who first presented with decreased level of consciousness and tremor 1.5 yr ago. He was evaluated in Netherlands where the patient was labeled as cirrhosis. All workup for finding etiology of the disease was negative at that time

42 LAB: AST: 110 IU, ALT:74 IU, Alk Ph: 166 IU Total protein: 7.8 g/dl, albumin: 3 g/dl LDH=580 Viral markers=negative PT: 17 sec (control 12.5)

43 LAB: HBV PCR: -ve HCV PCR: -ve Autoimmune markers: -ve Copper and ceruloplasmin: normal

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45 Iron Profile Serum Fe: 168 mg/dl TIBC: 180 mg/dl Fe saturation Index: 93% Ferritin: 1582

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48 Pathology In spite of the pathology report, the diagnosis of Hemochromatosis was not made. Probably because the patient was leaving for Iran. In Iran, further workup and another biopsy was done

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52 Genetic Study Genotyping for Hemochromatosis Genotyping analysis for Hemochromatosis: Blood sample sent to Sweden HFE-gene--- Cys 282 tyr mutation=negative. His 63 ASP Gene Mutation=Negative = Negative

53 Admission The patient was finally admitted with encephalopathy and severe ascites The Hgb at admission was 12.3

54 Phlebotomy Multiple phlebotomies were performed and the Hgb dropped to 9.8 There was only minimal improvement The patient was discharged without much improvement

55 Follow up Postphelebatomy The encephalopathy gradually progressed. He become agitated and confuse Ascites progressed. He died while in hepatic come 2 months after phelebatomy

56 Final diagnosis Hereditary Ferroportin disease hepatic type or Mutations in the transferrin receptor 2 gene ( TfR2)

57 Case 1 presentation 24 year old worker from Kermanshah presented because of hyperpigmentation of skin of face and weakness and occasional dyspnia x 3 months. His brother has died of liver failure and cardiac disease at age of 25. He also gave history of excessive red meat in his diet (even in breakfast) during last 3 years.

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60 Paraclinical investigation Abd Sono.: Mild splenomegaly Cardia Echo:Normal Ct-Scan of Abdomen: Diffuse hyperdense enlarged liver with normal spleen density

61 Hyperdense liver with normal spleen density in Ct scan

62 Hyperdense liver with normal spleen density in Ct scan

63 MRI

64 MRI at the time of diagnosis on bahman 1389

65 MRI

66 Lab Hb=14.2 esr=24,platelate= wbc=4500 Hb electerophoresis =Normal AST=65,ALT=78,GGT=304,Alkaline phos=570 Pt=12/12,APF=1.7 Total bil1.2 Direct=0.7,Ceruloplasmin=24. Ferretin>2000,TIBC=215 Fe=340 TIBC=215 Transferrin Saturation>85%

67 Diagnosis Juvenile Hemochromatosis probably one of the followig mutations:hamp,hjv or BMP6

68 Treatment Venosection 500 cc /4 weeks Responded very well after 3 phelebatomy ferretin=700

69 Follow up one year later 89/9/29 Serum Ferritin 3240 Ast=34 alt=62 hb=14.3 Her 42 sister develop Ferretin level=4573

70 Follow up two year later 90/11/29 Serum Ferritin=245 Ast=31 alt=22 hb=14.3

71 Follow up 91/10/15 Ferritin=150 Hb=14.5 Doping well Asymptomatics

72 Reza Malekzadeh DDRC/TUMS

73 HJV:p.C89R hetero II-10 II-11 HJV:p.C89R hetero HFE:p.V295Ahetero III-1 III-3 III-5 III-7 III-9 III-10 III-11 III-13 HJV:p.C89R hetero HFE:p.V295Ahetero n.d. HFE:p.V295A hetero HJV:p.C89R HOMO HJV:p.C89R HOMO HFE:p.V295A hetero n.d. HJV:p.C89R hetero n.d.