Alcoholic/Nonalcoholic/Inherited Liver Disease Flashcards Preview

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Flashcards in Alcoholic/Nonalcoholic/Inherited Liver Disease Deck (65)
1

Alcoholic Liver Disease: Epidemiology

-up to 41% of liver disease in Native Americans
-as high as 65% of all deaths from chronic liver disease in Native Americans
-24% of chronic liver disease (40% deaths from cirrhosis)
-hospitalizations costs b/w $600 million and $1.8 billion/year

2

Ethanol Use in US

63% >18 drink
top 20% drink 80% of ethanol
top 2.5% drink 27% of ethanol
alcohol dependence/abuse 7.4% (11% men, 4% women)

3

Alcoholic Liver Disease

-steatosis
-alcoholic hepatitis
-alcoholic cirrhosis (hepatocellular carcinoma, cholangiocarcinoma)

4

Alcohol in Alcoholic Liver Disease

Ethanol >40-80gm/day
>5 year
(12gm is 12oz beer, 4oz wine, 1oz liquor)

5

Risk of Cirrhosis

3 drinks/day in women
differences in volume of distribution
dec. gastric alcohol dehydrogenase activity, particularly in younger adults
-differences in first pass metabolism

6

Men >6 or >10 drinks per day

only 9% ALD 6.4% cirrhosis
only 11.8% 8% cirrhosis

7

Alcoholic Hepatitis

-40-60 years old
->80 gm/d > 5 years
-often >5 years
-rapid onset of jaundice
-fever, muscle wasting, ascites
-hepatomegaly with tenderness
-AST, ALT rarely over 300
-AST > 2x ALT
-frequent leukocytosis
-elevated INR
-prevalence unknown
-approximately 20% of 1604 alcoholic patients undergo liver biopsy

8

Alcoholic Hepatitis: Pathogenesis

-many proposed mechanisms of ethanol induced injury
-few animal models
-no one theory accepted

9

Alcoholic Hepatitis: Genetics

-concordance rate for alcoholic cirrhosis 3x higher in monozygotic twins than dizygotic twins
-in East Asians, functional polymorphisms of ADH2*1 gene were associated with increased susceptability to ALD
-in caucasians, the only replicated association is the TNF-alpha 238 polymorphism and ALD

10

Risk of Alcoholic Cirrhosis

1% >30-60gm/d
5.7% >120gm/d

11

Alcoholic Cirrhosis: Mechanisms

-ethanol, acetylaldehyde cause intestinal injury and increased permeability resulting in endotoxemia
-endotoxemia results in an inflammatory response by Kupffer cels

12

Two Hit Theory: Alcoholic Cirrhosis

1st Hit: Fatty Liver
-oxidative stress, inc. NADH/NAD ration, obesity and DM (genetics/diet), fat sensitizes liver to 2nd hit
2nd Hit: inflammation & necrosis, oxidative stress/hypoxia/immunological reaction

13

Alcoholic Hepatitis Predictors of Survival

-Maddrey Score
-Glasgow Alcoholic Hepatitis Score
-Model for End-Stage Liver Disease (MELD)

14

Advanced Liver disease in Alcoholics

-Hep C
-Hemochromatosis
-Alpha one antitrypsin deficiency

15

Ethanol + Hepatitis C

42% HCV
22% HCV + Ethanol
8% Ethanol

16

Ethanol + Hemochromaosis

-15% of patients with hemochromatosis had ethanol abuse (>80gm/d)
-ethanol abuse associated with advanced fibrosis with hemochromatisos
-inc. cirrhosis and shorter survival than those without ethanol abuse

17

Ethanol + HFE mutations

conflicting data
-patients with ALD + C282Y mutations had more advanced fibrosis and cirrhosis
-HFE Heterozygousity "likely play some role in inc. iron loading and liver injury"

18

Ethanol + HFE

-alcoholic cirrhotic patients with heterozygous C282Y mutations had increased hepatic iron scores and higher rates of HCC

19

Ethanol + A1AT deficiency

-2.7% with phenotype (Caucasian Americans)

20

Alpha one Antitrypsin Deficiency

MZ or ZZ
-chronic hepatitis (8% alcoholic)
-cirrhotic (41% alcoholic)

21

Ethanol + Obesity

-ethanol patterns, obesity and associated hyperglycemia are the most important environmental factors determining ALD risk

22

Treatment of Alcoholic Liver Disease

-abstinence
-optimize nutrition
-pentoxifylline (TNF alpha inhibitor)
-immunosuppression with corticosteroids in select patients
-LIVER TRANSPLANT

23

Spectrum of Alcoholic Liver Disease

-steatosis
-perivenular fibrosis (central vein)
-alcoholic hepatitis
-sub-sinusoidal fibrosis
-cirrhosis
-hepatocellular carcinoma

24

Macrovesicular

-lipid filled vesicle is larger than the nucleus

25

Nonalcoholic Fatty Liver Disease

-acquired liver disease in children & adults
-inc. w/epidemic of obesity in US
-macrovesicular hepatic steatosis
-ethanol <20gm per day

26

2 conditions of Nonalcoholic fatty liver disease

1. Steatosis
2. Non-Alcoholic Steatohepatitis (NASH)
-fatty liver, fibrosis and cirrhosis described in obease patients, (NASH was originally separate)

27

Obesity

-excess body fat in relation to lean body mass
-BMI > 30
-BMI = weight/height^2

28

Nonalcoholic Fatty Liver Disease: Prevalence

-NAFLD: 20-30% of adults, 10% kids
-by 2025, over 25 million Americans are predicted to have NAFLD related to liver disease
-next epidemic for liver disease
Fatty Liver: 10-15% of normal individuals
-70-80% of obese
NASH: 3% of normal, 15-20% of morbidly obese (BMI>35)

29

NAFLD associated with?

-obesity
-Type 2 Diabetes
-Hyperlipidemia
-Metabolic Syndrome

30

Nonalcoholic Fatty Liver Disease: Epidemiology

-Race/Ethnicity: mexican americans have the highest africans lowest
-Gender: initially more women, now 50/50
-Familial component: diet, genetics

31

Pediatric NAFLD

-10% of kids
-leading cause of pediatric liver disease
130 with liver biopsy: median age 12, 87% had fibrosis, 20% had bridging fibrosis
-in 100 with NASH: 8% advanced fibrosis, 3% cirrhosis

32

Other causes of NAFLD

1. Nutritional Abnormalities: total parenteral nutrition, starvation, refeeding
2. Metabolic Diseases: abetalipoproteinemia, hypobetalipoproteinemia
3. Occupational Chemical Exposure
4. Drugs: tamoxifen, corticosteroids, amiodarone, methotrexate, anti-retroviral therapy
5. Surgery: rapid, excessive wt loss (jejunoileal bypass)

33

Natural History of NAFLD

-fatty liver: limited progression
-NASH: 30-40% with advanced fibrosis
10-15% with cirrhosis
-NASH induced cirrhosis is an increasing cause of Hepatocellular Carcinoma

34

NAFLD: Pathogenesis

-normally triglycerides incorporated into chylomicrons (travel via lymphatics to peripheral fat), hydrolyzed to free fatty acids (stored in liver, oxidized by mirochondria (triglyceride/cholesterol formation))
-Steatosis: a result of disturbed balance (more lipogenesis/increased FFA)

35

NAFLD: Pathogenesis (insulin resistance)

-insulin promotes uptake of glucose (stored as glycogen)
-inhibits lipolysis
-increased levels of insulin lead to increased lipogenesis, increased FFA
-increased mitochondrial fatty acid oxidation (free radical formation & damage)

36

NAFLD: obesity

-increase in synthesis of free fatty acids (FFA)
-decrease in oxidation of FFA
Insulin Resistance
-increase in adipose tissue lipolysis, increased FFA

37

NAFLD: increased FFA leads to?

-fatty liver
-increased oxidative stress, increased free radicals, direct liver injury

38

NAFLD: 2 hit hypohesis

1. hepatic fat accumulation
2. oxidative stress via lipid peroxidation and free radicals

39

Concomitant Liver Desease

-Hep C + NASH
-Hemochromatosis + NASH
-Alpha 1 antitrypsin deficiency + NASH
-alcohol + NASH

40

NAFLD Clinical Features

-most have no symptoms or signs of chronic liver disease
-nonspecific symptoms: fatigue

41

Treatment of NAFLD

-weight reduction (10%)
-if diabetic: control
-if hyperlipidemic: treat (inc. cardiac risk)
-no magic meds

42

Regulation of Fe absorption and release?

-Hepcidin
-Ferroportin (baso-lateral surface of enterocytes/macrophages; regulates Fe export
-HFE gene protein (exact mechanism of action unknown)
-HJV, BMP 6

43

Hepcidin

-Principal iron-regulatory hormone
-Regulation of Hepcidin release is the central mechanism in the pathogenesis of HH
-Expressed predominantly in hepatocytes
-Binds to ferroportin on basolateral surface of enterocytes and macrophages

-Ferroportin internalized, inhibition of Fe release
-Hepcidin expression is induced by excess iron and inflammation; expression decreased in fe deficiency, ineffective erythropoeisis
-Mutations in HFE decrease Hepcidin expression leading to increased intestinal Fe absorption via up-regulation of ferroportin

44

Genetic Hemochromatosis


Most common genetic disorder affecting Caucasians

1:200-250 in individuals of Celtic/Nordic origins

Several types, most common (Type 1) is related to HFE gene mutations

Inappropriately increased uptake of dietary iron

Serum Iron is offloaded into tissues with High Transferrin Receptors Liver /Heart/Pancreas/Thyroid

Increased oxidative stress generates Free radicals

45

HFE gene mutations

85-90% due to mutations in HFE gene
HFE gene defect described in 1996
C282Y/C282Y (80-85% of HH): G to A mis-sense mutation (tyrosine for cysteine)
Other gene mutations: H63D, S65C homozygotes not associated with iron overload
C282Y/H63D or C282Y/S65C may be associated with iron overload

46


Clinical Features of Hemochromatosis (Type I)

Phenotypic expression (70%), End organ damage in only 10%

Adult onset > 40 yrs men > 50 yrs women

General: fatigue, arthritis (most common)

Liver: Cirrhosis, hepatocellular carcinoma

Heart: Restrictive Cardiomyopathy

Pancreas: diabetes (formerly called bronze diabetes)

Arthritis (second/third metcarpophalangeal joints)

47

Type II Hemochromatosis (HJV)

Excess iron due to lack of Hepcidin (mutation at HAMP & HJV genes)
Age of onset 10-15 yrs
More cardiac involvement

48

Hemochromatosis Type III & IV

Type III – Transferrin Receptor mutation
( similar to type 1)
Type IVa and Type IVb caused by Ferroportin mutation
Only few cases described worldwide

49

Diagnosis of Hemochromatosis Role of Liver Biopsy

Confirms Excess tissue Iron Hepatic iron Index ( HIC/age) > 1.9
Assess the degree of Liver injury in patients with abnormal LFTs and Ferritin > 1000
- Diagnose Hemochromatosis in the absence of HFE mutation (type II, III)

50

Iron Overload (Secondary-Non Genetic )

Ineffective erythropoeisis (Thalassemia, Sideroblastic anemia)

Parenteral iron overload (long term HD, blood transfusions)

Chronic liver disease

Aceruloplasminemia

Congenital atransferrinemia

51

Screening for HFE

Recommended for all first degree relatives
Check Ferritin/TS and HFE mutation analysis
For children of a pro-band, sufficient to check
other parent, if normal then children are
heterozygotes and do not need further testing

Homozygotes/compound heterozygotes with elevated Ferritin should initiate therapeutic phlebotomies; If Ferritin levels are normal then monitor Fe studies annually

52

Treatment Hemochromatosis

Focus is on removing excess iron
( irrespective of gene mutation)

Phlebotomy - may need several weeks

Iron Chelating Agents:
( Binds Iron and removed through urine)
-Desferoxamine Intravenous
-Deferasirox (Exjade) Oral
- useful when patient has low hemoglobin
(Thalassemia, sickle cell)

Avoid vitamin C (increases Fe absorption)

Decrease alcohol intake

Decrease Dietary iron intake (no longer recommended)

-Avoid Undercooked seafood risk of Vibrio vulnificus
-Patient are high risk of infections with siderophilic
“iron loving” Bacteria Listeria, Yersinia

53

Wilson’s Disease

Autosomal recessive disorder
1st described in 1912 by Kinnear Wilson
Excessive Cu deposition
Target Organs (Major)
Liver: Chronic Hepatitis, Cirrhosis
Brain: Basal Ganglia, Psychiatric
Kidneys: Proximal tubular disease
ATPase Deficiency

54

Clinical Features of Wilson's Disease

Liver disease (presents earlier in life); wide spectrum (Abnormal LFTs, Cirrhosis, ALF)
Neurological disease (Parkinson like symptoms; tremor, dysarthria, dystonia, lack of motor coordination, spasticity, dysphagia)
Psychiatric disease
Other organ involvement (Cardiomyopathy, Pancreatitis, Osteoporosis, Arthritis, Nephrolithiasis)
Kayser-Fleisher Ring (deposti in cornea)

55

Fulminant Liver Failure

Acute presentation of a Chronic Disease

Clinical
Liver Failure: Encephalopathy, Coagulopathy
Hemolytic Anemia ( Coomb's negative)
Low serum Alkaline Phosphatase; ALP/Bil < 2
AST/ALT < 2000

Treatment
Only Treatment is Liver Transplantation

56

When to suspect Wilson’s Disease

Any patient < 40 yrs with elevated AST/ALT
Neuropsychiatric disease with liver disease
Any young patient with liver failure
Presentation at age < 5 yr or > 40 yr is unusual but possible

57

Wilson Disease: Diagnosis

Serum Ceruloplasmin
- ( Normal 20-50 mg/dl)
- 95% of Wilson disease pts have low ceruloplasmin
- Can be low in patients with decompensated liver disease of any etiology
- levels < 5 mg/dl are highly suggestive of underlying Wilson’s
-Serum total Cu - 3.15x Ceruloplasmin = non Ceruloplasmin (free) Cu
-Total Copper is usually low (due to low Ceruloplasmin)
-Free Copper >25 µgm/dl is typical of Wilson’s
-Mild increase in other cholestatic liver diseases
Liver Copper Concentration
> 250 µgm/gram
False Negative
Advanced liver disease with severe fibrosis

58

Genetic Testing for Wilson's Disease

Difficulties
1. There are multiple mutations causing defective protein ( unlike Hemochromatosis where a single mutation causes the disease)
2. Polymorphism of normal gene ( non disease causing mutations)
3. So genetic testing is feasible only if you have an index case ( family member)

59

Treatment: Wilson’s Disease

Medical
1. Chelating agents
Penicillamine
Trientene
Tetrathiomolybdate
2. Zinc

Liver Transplantation

60

Wilson’s Disease: Drugs

Penicillamine (chelates copper)
10% may not tolerate due to side effects
Pyridoxine
SE: Lupus, hepatotoxicity, neuropathy, GI side effects

Trientene (chelates copper)
250 qid, SE: sideroblastic anemia

Zinc (decreases the absorption of Copper)
SE: GI symptoms

Trientene + Zinc is probably the Rx of Choice

61

Alpha 1 ANTI TRYPSIN

A protein (314 Amino Acids) produced by the Liver
Neutralizes neutrophil elastase activity
Proper secretion from liver is essential for normal serum levels

62

α 1AT (Terminology)

Phenotype: the two types of molecules from each parent

Example: Phenotype MZ
One molecule is M (one parent) and
Second molecule is Z (from other parent)

Phenotypes: MM,MZ, MS, ZZ, SS, ZZ

Liver disease is seen only with ZZ type and some SZ type

63

When to suspect Alpha 1 Anti-trypsin?
Diagnosis?

-Cirrhosis of undetermined etiology

-Emphysema with liver disease

-Emphysema (especially in non smokers)

Diagnosis
-Phenotype disease phenotype is ZZ

-Liver Biopsy showing Alpha 1 AT granules

64

Treatment for Alpha 1 Anti-trypsin?

STOP SMOKING

1. Replacement α AT (IV infusion)
Useful for emphysema
Not useful for liver disease

2. Rx of patient with cirrhosis
Liver transplantation

65

Impact of Liver Transplantation

1. Hemochromatosis
Disease can theoretically recur (clinically not seen)
No Impact on extrahepatic sites (cardiac)
2. Wilson’s Disease
OLT cures the disease, No recurrence
Neurological disease may improve
3. Alpha 1 Antitrypsin Deficiency
OLT cures the hepatic disease
Emphysema is irreversible
( further pulmonary damage may be prevented)