The aging liver

1. TheThe Aging LiverAging Liver
Dr. Tarek ShetaDr. Tarek Sheta
Lecturer of internal medicineLecturer of internal medicine
Mansoura Faculty of MedicineMansoura Faculty of Medicine
TheThe Aging LiverAging Liver
Dr. Tarek ShetaDr. Tarek Sheta
Lecturer of internal medicineLecturer of internal medicine
Mansoura Faculty of MedicineMansoura Faculty of Medicine

2. Outline
 Normal Liver
 Morphological changes with aging
 Vascular changes with aging
 Metabolic changes with aging
 Relationship between liver disease and aging
 Normal Liver
 Morphological changes with aging
 Vascular changes with aging
 Metabolic changes with aging
 Relationship between liver disease and aging

3. The Normal Liver…in brief
 Largest gland & ‘solid’ organ.
 Up to 1.5kg in men & 1.3kg in women.
 Holds up to 13% blood volume.
 2 lobes; right 2/3rd > left 1/3rd
 Largest gland & ‘solid’ organ.
 Up to 1.5kg in men & 1.3kg in women.
 Holds up to 13% blood volume.
 2 lobes; right 2/3rd > left 1/3rd

4. The Normal Liver…in brief
 2 distinct blood supplies
– Arterial – Hepatic arteries
– Venous – Portal vein
 2/3rd of liver is parenchymal; 1/3 is
biliary tract.
 Average lifespan of a hepatocyte is ~
150 days.
 2 distinct blood supplies
– Arterial – Hepatic arteries
– Venous – Portal vein
 2/3rd of liver is parenchymal; 1/3 is
biliary tract.
 Average lifespan of a hepatocyte is ~
150 days.

5. Effect of Aging on the liver
 Unlike the heart, brain and kidneys, the liver is
not affected by common degenerative
diseases such atherosclerosis, diabetes and
hypertension.
 The liver is spared these diseases probably as
a result of its dual blood supply, abundant
reserve and high regenerative capacity.
 Unlike the heart, brain and kidneys, the liver is
not affected by common degenerative
diseases such atherosclerosis, diabetes and
hypertension.
 The liver is spared these diseases probably as
a result of its dual blood supply, abundant
reserve and high regenerative capacity.

6. Morphological Changes of Ageing
Liver size
 The liver has a remarkable ability to
regenerate and maintain function
during the ageing process. There are,
however, changes on a cellular and
physiological level which reduce the
overall function of the liver.
Liver size
 The liver has a remarkable ability to
regenerate and maintain function
during the ageing process. There are,
however, changes on a cellular and
physiological level which reduce the
overall function of the liver.

7. Morphological Changes of Ageing
 Despite compensatory cell hypertrophy,
in response to the decreased number of
hepatocytes seen with ageing, liver size
reduces by 25% between the age of 20
and 70, with a 33% reduction of hepatic
blood flow in over 65 year olds
 Despite compensatory cell hypertrophy,
in response to the decreased number of
hepatocytes seen with ageing, liver size
reduces by 25% between the age of 20
and 70, with a 33% reduction of hepatic
blood flow in over 65 year olds

8. Morphological Changes of Ageing
 The characteristic
gross change that
occurs in the aging
liver is “brown
atrophy”. The
darkened colour is
due to
accumulation of
lipofuscin pigment
within hepatocytes.
 The characteristic
gross change that
occurs in the aging
liver is “brown
atrophy”. The
darkened colour is
due to
accumulation of
lipofuscin pigment
within hepatocytes.

9. Morphological Changes
 ↑ Lifespan of hepatocytes
 ↑ Nuclei size & polyploidy
 ↑ Mitochondrial volume
 ↑ Lifespan of hepatocytes
 ↑ Nuclei size & polyploidy
 ↑ Mitochondrial volume

10. Morphological Changes
 ↑ Intracellular protein
 ↑ Inter-hepatocyte space
- (↑ collagen)
 ↑ Lipofuscin deposition
- (↓ intracellular proteinolysis)
 ↑ Intracellular protein
 ↑ Inter-hepatocyte space
- (↑ collagen)
 ↑ Lipofuscin deposition
- (↓ intracellular proteinolysis)

11. Morphological Changes
At the microcirculatory level, liver
sinusoids demonstrate endothelial
thickening and loss of
fenestrations, referred to as
pseudocapillarisation.
At the microcirculatory level, liver
sinusoids demonstrate endothelial
thickening and loss of
fenestrations, referred to as
pseudocapillarisation.

12. Morphological Changes
 Kupffer cells,important in the elimination
of endotoxin and tumour cells, suffer a
decline in phagocytic function with
aging.
 At the ultrastructural level, hepatocytes
demonstrate a decline in rough
endoplasmic reticulum and mitochondria
 Kupffer cells,important in the elimination
of endotoxin and tumour cells, suffer a
decline in phagocytic function with
aging.
 At the ultrastructural level, hepatocytes
demonstrate a decline in rough
endoplasmic reticulum and mitochondria

13. Vascular Changes
 ↓ Liver blood flow (by ≤ 35%) [Normal =
~1.5L/min]
 ↓ Liver perfusion (≤ 10%)
i.e. blood flow per unit vol. of liver tissue
 ↓ Liver blood flow (by ≤ 35%) [Normal =
~1.5L/min]
 ↓ Liver perfusion (≤ 10%)
i.e. blood flow per unit vol. of liver tissue

14. Response to Injury
The liver is generally quite
tolerant of both acute and
chronic insults. It is capable of
recovering from interruption of
its blood supply and
oxygenation for periods lasting
one hour
The liver is generally quite
tolerant of both acute and
chronic insults. It is capable of
recovering from interruption of
its blood supply and
oxygenation for periods lasting
one hour

15. Response to Injury
However, as the liver ages, its
ability to regenerate after toxic
injury is impaired—the
regenerative response is
complete but it takes longer.
However, as the liver ages, its
ability to regenerate after toxic
injury is impaired—the
regenerative response is
complete but it takes longer.

16. Response to Injury
The reduced ability of the older liver
to regenerate may have an impact
on the natural history of some liver
diseases.
The rate of progression to cirrhosis
in patients with chronic hepatitis C
is directly associated with age at
the time of contracting the infection
The reduced ability of the older liver
to regenerate may have an impact
on the natural history of some liver
diseases.
The rate of progression to cirrhosis
in patients with chronic hepatitis C
is directly associated with age at
the time of contracting the infection

17. Metabolic Changes
 ↓ Liver cholesterol synthesis
 ↓ Bile acid synthesis
 ↑ Secretion of cholesterol into bile
– ?? Latter two as possible cause for
↑ gallstones with ageing
 ↓ Liver cholesterol synthesis
 ↓ Bile acid synthesis
 ↑ Secretion of cholesterol into bile
– ?? Latter two as possible cause for
↑ gallstones with ageing

18. Metabolic Changes
 No clinically significant change of LFTs
– But minor & transient changes
– E.g. in acute illness, heart failure
– In particular, mild ↑ Alkaline Phosphatase
• ?? Acute phase protein response, if
transient rise
• But if persistent, could indicate possible
liver dx.
 No clinically significant change of LFTs
– But minor & transient changes
– E.g. in acute illness, heart failure
– In particular, mild ↑ Alkaline Phosphatase
• ?? Acute phase protein response, if
transient rise
• But if persistent, could indicate possible
liver dx.

19. Metabolic Changes
 Minimal change to Blood Urea Nitrogen
– But urea synthesis is inversely
related to age
 Minimal change to Blood Urea Nitrogen
– But urea synthesis is inversely
related to age

20. Hepatic Drug Metabolism
 The hepatic elimination of galactose and
caffeine is significantly reduced in the
elderly population.
 A study of liver biopsies from a large,
heterogenous population has shown a
gradual decline in the hepatocyte
concentration of P450 enzymes with
age.
 The hepatic elimination of galactose and
caffeine is significantly reduced in the
elderly population.
 A study of liver biopsies from a large,
heterogenous population has shown a
gradual decline in the hepatocyte
concentration of P450 enzymes with
age.

21. Hepatic Drug Metabolism
 ↓ Liver Enzyme Function
– Not due to ↓ enzyme deficiency
– Due to ↓ Liver blood flow
– Affects both Oxidative & Conjugative
metabolism
 ↓ Liver Enzyme Function
– Not due to ↓ enzyme deficiency
– Due to ↓ Liver blood flow
– Affects both Oxidative & Conjugative
metabolism

22. Hepatic Drug Metabolism
 Consequent ↓ drug clearance
– Up to 50% for some drugs
– Age alone might account for 10
– 30%
– Other influences
Diet / Nutrition
Smoking
 Consequent ↓ drug clearance
– Up to 50% for some drugs
– Age alone might account for 10
– 30%
– Other influences
Diet / Nutrition
Smoking

23. Hepatic Drug Metabolism

24. Specific liver diseases in the
elderly
GENERAL RULESGENERAL RULES
 The presence of an advanced liver disease or
cirrhosis is more frequent in old patients as
the first clinical presentation.
 No liver disease is specific to old age
 Onset is more insidious in older patients.
 Age-adjusted mortality is often greater in the
elderly.
GENERAL RULESGENERAL RULES
 The presence of an advanced liver disease or
cirrhosis is more frequent in old patients as
the first clinical presentation.
 No liver disease is specific to old age
 Onset is more insidious in older patients.
 Age-adjusted mortality is often greater in the
elderly.

25. Specific Liver Diseases:
Prevalence mildly ↑ with age
– Bacterial
infections
(Liver
Abscess)
– Primary Biliary
Cirrhosis
– Hepatocellular
Carcinoma
– Non-Alcoholic Cirrhosis
– Obstructive Jaundice
• Choledocholithiasis
• Malignant
Obstruction
– Bacterial
infections
(Liver
Abscess)
– Primary Biliary
Cirrhosis
– Hepatocellular
Carcinoma
– Non-Alcoholic Cirrhosis
– Obstructive Jaundice
• Choledocholithiasis
• Malignant
Obstruction

26. Viral hepatitis
HEPATITIS A
Although hepatitis A is rare in
patients over 65 years of age the
ratio of mortality to notifications
rises dramatically with
advancing age.
HEPATITIS A
Although hepatitis A is rare in
patients over 65 years of age the
ratio of mortality to notifications
rises dramatically with
advancing age.

27. HEPATITIS B
acute hepatitis B is rare in the
elderly population,
Hepatitis B vaccination
produces a lower antibody
response with advancing age,
possibly due to a lack of
antibody producing B cells.
acute hepatitis B is rare in the
elderly population,
Hepatitis B vaccination
produces a lower antibody
response with advancing age,
possibly due to a lack of
antibody producing B cells.

28. HEPATITIS C
Several studies of community
acquired hepatitis C, including a
high proportion of elderly patients,
suggest that it has a rather benign
course.
It seems likely that many elderly
individuals remain asymptomatic
from HCV even if they may have
acquired it 20 or more years before.
Several studies of community
acquired hepatitis C, including a
high proportion of elderly patients,
suggest that it has a rather benign
course.
It seems likely that many elderly
individuals remain asymptomatic
from HCV even if they may have
acquired it 20 or more years before.

32. Drug-induced liver injury
 ↑ Prevalence of drug-induced injury
 An important consideration in caring for
the elderly is the high incidence of
polypharmacy and drug reactions in this
age group, so that in general, lower
doses of hepatically- metabolised drugs
are indicated compared to a younger age
group.
 ↑ Prevalence of drug-induced injury
 An important consideration in caring for
the elderly is the high incidence of
polypharmacy and drug reactions in this
age group, so that in general, lower
doses of hepatically- metabolised drugs
are indicated compared to a younger age
group.

33. PRIMARY BILIARY CIRRHOSIS
among initially asymptomatic
antimitochondrial antibody (AMA)
positive patients, in elderly
individuals, often picked up during
screening for other autoantibodies,
may show a particularly slow and
indolent course.
among initially asymptomatic
antimitochondrial antibody (AMA)
positive patients, in elderly
individuals, often picked up during
screening for other autoantibodies,
may show a particularly slow and
indolent course.

34. Alcoholic liver disease
 There are important pharmacokinetic differences
in ethanol metabolism between older and younger
subjects.
 most patients present with severe alcoholic liver
disease in their fifth or sixth decade.
 Among those who do present to hospital with
alcoholic liver disease over 60 years of age,
symptoms are more severe with a higher
frequency of presentation with complications of
portal hypertension, and prognosis is directly
related to age.
 There are important pharmacokinetic differences
in ethanol metabolism between older and younger
subjects.
 most patients present with severe alcoholic liver
disease in their fifth or sixth decade.
 Among those who do present to hospital with
alcoholic liver disease over 60 years of age,
symptoms are more severe with a higher
frequency of presentation with complications of
portal hypertension, and prognosis is directly
related to age.

35. NASH

36. AUTOIMMUNE HEPATITIS
generally affect younger women -
only 20% of cases of autoimmune
hepatitis occur in patients older
than 65 years.
The prognosis in this age group is
excellent, as the disease generally
follows a more benign course that
rarely leads to cirrhosis.
generally affect younger women -
only 20% of cases of autoimmune
hepatitis occur in patients older
than 65 years.
The prognosis in this age group is
excellent, as the disease generally
follows a more benign course that
rarely leads to cirrhosis.

37. Gall Bladder stones
There is a high prevalence of
gallstones among old people, in
particular among females.
Complicated by diminished
perception of pain as well as
relative lack of physical
findings.
There is a high prevalence of
gallstones among old people, in
particular among females.
Complicated by diminished
perception of pain as well as
relative lack of physical
findings.

38. Primary hepatocellular
carcinoma
At least in Western countries HCC
may be considered a disease
associated with aging.
it has been demonstrated recently
that in an experimental model there
was a twofold increase in the
number of DNA bases damaged by
oxidative stress in advanced age.
At least in Western countries HCC
may be considered a disease
associated with aging.
it has been demonstrated recently
that in an experimental model there
was a twofold increase in the
number of DNA bases damaged by
oxidative stress in advanced age.

39. Primary hepatocellular
carcinoma
 HCC incidence had been low before age 40 as
it increases progressively with older age and
peaks in incidence around ages 70–75.
 The incidence of HCC drops steadily and
significantly in individuals older than 75, and
up to 90+.
 Currently, with the rising rates of HCC, there
is a shift of incidence from typically elderly
patients to relatively younger patients
between ages 40 and 60 .
 HCC incidence had been low before age 40 as
it increases progressively with older age and
peaks in incidence around ages 70–75.
 The incidence of HCC drops steadily and
significantly in individuals older than 75, and
up to 90+.
 Currently, with the rising rates of HCC, there
is a shift of incidence from typically elderly
patients to relatively younger patients
between ages 40 and 60 .

40. Ascites
 There are no age-related absolute
contraindications to diuretics; however, some
adverse effects may be more severe with
advancing age.
 Elderly patients with cirrhosis are more likely
to suffer from disturbed fluid balance
homeostasis, leading to orthostatic
hypotension as a result of low intra-vascular
volume, exacerbated by diuretic use.
 Furthermore, older patients prescribed
diuretics are at increased risk of incontinence.
 There are no age-related absolute
contraindications to diuretics; however, some
adverse effects may be more severe with
advancing age.
 Elderly patients with cirrhosis are more likely
to suffer from disturbed fluid balance
homeostasis, leading to orthostatic
hypotension as a result of low intra-vascular
volume, exacerbated by diuretic use.
 Furthermore, older patients prescribed
diuretics are at increased risk of incontinence.

41. Hepatic encephalopathy
 there are some pitfalls in making the
diagnosis of hepatic encephalopathy since
other conditions can mimic the findings:
- Organic brain syndrome: eg cereb
astherosclerosis.
- cognitive and memory impairment
- delirium due to medication adverse events or
“polypharmacy” and drug interactions
- uremia due to renal failure
 there are some pitfalls in making the
diagnosis of hepatic encephalopathy since
other conditions can mimic the findings:
- Organic brain syndrome: eg cereb
astherosclerosis.
- cognitive and memory impairment
- delirium due to medication adverse events or
“polypharmacy” and drug interactions
- uremia due to renal failure

42. Hepatic encephalopathy
Care should be taken when
treating the elderly with
laxatives; malabsorption,
dehydration, electrolyte
imbalance and faecal
incontinence are all more likely
to occur
Care should be taken when
treating the elderly with
laxatives; malabsorption,
dehydration, electrolyte
imbalance and faecal
incontinence are all more likely
to occur

43. Fulminant Hepatitis
mortality after fulminant hepatic
failure is higher in the aged
population regardless of the
etiology of the hepatic injury,
mortality after fulminant hepatic
failure is higher in the aged
population regardless of the
etiology of the hepatic injury,

44. - Advanced age is not considered a
contraindication to liver
transplantation
- but recipients older than 60 years
with poor hepatic synthetic function
and comorbidity show a worse
prognosis with lower survival
rates.
Liver Transplantation
- Advanced age is not considered a
contraindication to liver
transplantation
- but recipients older than 60 years
with poor hepatic synthetic function
and comorbidity show a worse
prognosis with lower survival
rates.

45. Liver Transplantation
livers from older donors that are
transplanted into hepatitis C
infected recipients are more likely
to be damaged by the virus
compared to younger grafts.
livers from older donors that are
transplanted into hepatitis C
infected recipients are more likely
to be damaged by the virus
compared to younger grafts.

46. Liver Transplantation
It has been suggested that the
marginal impairment of immune
function accompanying normal
aging may reduce the incidence of
allograft rejection and may allow
lower dosage of
immunosuppressive drugs in older
liver recipients.
It has been suggested that the
marginal impairment of immune
function accompanying normal
aging may reduce the incidence of
allograft rejection and may allow
lower dosage of
immunosuppressive drugs in older
liver recipients.

47. Liver resection
Age did not influence morbidity, in-
hospital mortality and survival of
patients undergoing hepatectomy.