CPC

1
CPC 6 Dark Voyage of the Fearless Eagle
Bridging the Gap. Where Clinical and Basic
Sciences Meet

• Khawar Shaikh, MD
• Fellow, Cardiovascular Diseases

Louisa Balazs, MD, PhD Associate Professor of
Pathology
Karl T. Weber, MD Professor of Medicine
2
A gentle summer breeze blew across the North Sea
as the Fearless Eagle (der Adler), prepared to
depart Hamburg in July, 1898.
3
This steamer would make its first voyage to East
Asiaa nonstop journey to Hong Kong that would
take several months.
4
Standing at the helm was Captain Tritthart, who
barked out instructions to his crew.
5
Young Dr. Bernhard Nocht made his way over to the
captain. Nocht, a naval physician, would care
for the ships crew while satisfying his
wanderlust to visit distant shores. He reported
that rations on board, including citrus fruit
from Spain, baked bread, fresh vegetables, and
fresh as well as canned meats, had passed his
personal inspection. Further, all hired men were
fit for the long journey. The arduous 60-day
voyage on the high seas proved uneventful and
import goods were delivered on time in early
September.
6
There followed a six-week stay in Hong Kong. The
Captain kept the crew mindful of the ships time
table. Asian exports had to be promptly loaded
for the return voyage. As added incentive, he
noted that by maintaining schedule the return
voyage would reach Germany in time for the
Christmas holiday.
7
Tritthart also searched for men who could serve
as stokers fueling the ships hungry furnace.
8
Twenty-three men would ultimately be hired, but
only after Bernhards physical examination had
pronounced them fit. All were of fine physique
and Bernhard had found no evidence of
communicable illnesses, such as measles,
scarlatina, tuberculosis or smallpox none had
body lice, dermal eruptions or were jaundiced and
none had cardiac murmurs, ascites, peripheral
edema or neurologic deficits. To accommodate
their dietary preferences Bernhard ordered crates
of dried fish and white rice for the journey to
Hamburg.
9
The Chinese crew would not begin work until the
steamer was back in Hamburg. They therefore
would be passengers on this return voyage. By
October 16 the Fearless Eagle was back at sea on
its way to Hamburg. No illnesses appeared among
European or Chinese crews during the uneventful
8-week voyage. By mid-December, and with the ship
bsck in its Hamburg port, the Hong Kong-based
crew was now actively involved in their
physically demanding chores aboard the steamer.
10
It was on December 26, that Bernhard found Song
Yang and Li Ming had taken ill. Song Yang
complained of poor appetite and malaise, nausea
and generalized weakness. There was a loss of
power in lower extremities with muscular atrophy
and with a slow deliberate gait he hobbled about
using ropes, hatches or dockhouses to steady
himself. He further reported numbness and a
prickling sensation to the soles of his feet.
11
In recent days, Li Ming had taken ill with
swollen facies and legs, a bounding, rapid pulse
and neck vein distention. Bernhard arranged for
both men to be admitted to a hospital. Li Ming
died soon after admission. Captain Tritthart
summoned Bernhard to his cabin to ascertain why
these men had taken ill. Bernhard reported
sadness and surprise at this unexpected turn of
events. The Chinese crew were presumptively
healthy and each had been carefully examined for
illness prior to their hire.
12
Food had not spoiled and water tanks were well
maintained. The steamer was in good sanitary
condition and did not harbor pestilence. If
these men had been ill with infection when they
came on board in Hong Kong, he could not discern
what disease had a latency period of some 70 days
and why others had not taken ill. Tritthart and
Nocht could only guess at the possibilities, but
infection seemed improbable. The Fearless Eagle
departed for Boston on December 27.
13
Out to sea but a few days, the steamer was
engulfed by the first of several hurricane-like
storms. The Chinese crew, barefoot and without
proper clothing, was not prepared for these
adverse conditions. Their exposure to the
elements was constant as they traversed the
flooded front deck several times daily to reach
their living quarters. They frequently suffered
upper respiratory infections.
14
It was January 8, 1899, two weeks after their
departure from Hamburg and 13 weeks since leaving
Hong Kong, that Wong Shown reported ill. His
legs, face and scrotum were swollen and he noted
pains in both calves and chest. Bernhard found
Wong to have a rapid but regular, bounding pulse
by percussion there was no evidence of cardiac
enlargement. Over ensuing days, compressive
dressings proved useful in reducing ankle and leg
edema.
15
Atrophy of leg and arm muscles became apparent
and Wong developed a progressive paralysis of his
lower extremities and remained confined to his
quarters for the remainder of the
journey. Perplexed and frightened, Bernhard
struggled to contain his sense of helplessness.
Crew members asked him to see Wong San on the
evening of January 19. Wong San was the fourth
member of the Chinese crew to fall ill, the third
with swollen facies and leg edema.
16
Pitting edema also involved the abdominal wall
and thorax and there was percussion dullness in
keeping with bilateral pleural effusions. Over
ensuing days Nocht applied compressive leg
dressings, warm poultices of aromatic scammony to
the chest, while feet were inuncted with oils of
cloves and mace mixed with oil of rose. Little
seemed to help. His desperation growing,
Bernhard turned to a decoction of Sarsaparilla
roots in the hopes of dispelling the evil humor
through sweat and urine.
17
An extract of aloes was used as a cathartic.
Despite these efforts, Wong San suddenly
collapsed and died the evening of February 1. Yet
another crew member, Wong Sui, was stricken on
January 29 in the same way as his coworker. His
symptoms were less advanced, but his fear
overwhelming. Violent storms again appeared to
further prolong the journey. On February 8, Wong
Sui, his feeble voice barely audible, attempted
to speak with fellow crew members as they left
guard duty.
18
He was found dead in his berth an hour later.
Bernhard noted that he had developed marked edema
of face, trunk and legs. Between February 16 and
mid-March, 1899, five additional members of the
Chinese crew would be stricken with the ailment
that featured facial and peripheral edema most
had rapid heart rate. All told and since the
departure of the Fearless Eagle from Hong Kong on
October 16, ten cases had appeared 5 had not
survived.
19
By early April and out of desperation, Captain
Tritthart arranged for the remainder of the
Chinese crew to be placed aboard a steamer bound
for East Asia and so ended the epidemic aboard
this steamer.
20
The 54-day voyage to Boston had taken longer than
expected. Exhausted and perplexed, Bernhard Nocht
and Captain Tritthart sat down to survey the
epidemic and circumstances that had befallen
their hardworking Chinese crew. There had been
several intrinsic difficulties. First, the crew
was reluctant to bring their ailments to
attention for fear of retribution. As a result,
they only presented when their illness and
symptoms were far advanced. Second, they did not
trust the European physician.
21
Third, detailed clinical evaluation had been
hampered by the weather, the crews obligatory
responsibilities and inadequate quarters for
health care. Finally, Bernhard admitted that his
understanding of the illness was hindered by
limited onboard medical literature. Nocht
provided his perspective. He focused on three
areas the crews living conditions, the climate
encountered during the voyage, and the crews
nutritional status.
22
The men had been provided larger-than-recommended
quarters that were well ventilated and this was
true for journeys between Hong Kong and Hamburg
and Hamburg to Boston. No prior Asian
inhabitants had occupied these quarters.
Tritthart added it was policy after each 6-week
voyage, that living quarters be disinfected
indeed prior to leaving Hamburg in December they
had also been painted. They concluded living
conditions could not have been contributory.
This could not be a place infection, an illness
endemic to a disease-laden ship.
23
The journey between Hamburg and Boston had been
prolonged by adverse weather and members of the
Chinese crew were not properly clothed and
regularly had taken ill with common colds. Could
this have made them more susceptible to the
illness? Drinking water was considered
noncontributory. It was available to all sailors
and was replenished during each voyage at ports
frequented regularly by many vessels.
24
Despite recommendations for a diverse diet, the
Chinese crew preferred their own rations that
included fish, white rice and various spices. A
separate kitchen had provided them privacy and
the opportunity to prepare their dietary intake
according to custom and preference. Rice
purchased for the crew was considered to be of
the highest quality.
25
The same could not be said for the fish. The
crew had preferred half-cooked fish and dried
fish. As adverse weather prolonged the voyage,
rations became low. Discovery of spoiled fish,
which the crew may have consumed, led to prompt
disposal. The crew rebuked recommended European
fare even though none of the Europeans aboard had
taken ill. The importance of fish to the
epidemic could therefore not be discounted. What
is your diagnosis and what is its causality?
26
Case I II

• Song Yang
• Poor Appetite, Malaise, nausea, generalized
  weakness (constitutional)
• Loss of power in LE, gait abnormality, numbness
  and prickling sensation in distal extremity
  (peripheral nerve symptoms)
• Li Ming
• Poor appetite, malaise, nausea, generalized
  weakness (constitutional)
• Loss of power in LE, gait abnormality, numbness
  and prickling sensation in distal extremity
  (peripheral nerve symptoms)
• Swelling of face legs, bounding pulse, neck
  veins (hyperdynamic circulation and volume
  overload
• Rapidly fatal

27
Case III IV

• Wong Shown
• Swelling of face legs (volume overload)
• Pains in calves chest
• Bounding pulse, no cardiomegaly, (hyperdynamic
  circulation)
• Progressive paralysis of lower extremities
• Wong San
• Swollen facies leg edema
• Bilateral pleural effusion
• Rapidly fatal

28
Differential diagnosis Part I

• Infectious Processes Less likely latency of 70
  days, no members of the European crew were
  involved (race specific), Hepatitis No jaundice,
  neuropathy
• Poisoning Arsenic Burning of fossil fuels and
  consumption of food smoking tobacco treated
  with Arsenic containing pesticides. Although it
  can cause peripheral neuritis and quadriplegia
  and delayed cardiomyopathy also characteristic
  are nail/skin changes and other keratin
  containing tissue changes, vasospasm-black foot
• Amyloidosis Peripheral neuritis and heart
  failure. Rapid course and absence of chronic
  disease. Race specific.
• Syphilis, Tertiary with AR and Tabes dorsalis
  (sporadic, healthy at screening)
• Chronic alcoholism

29
Differential Diagnosis Part II

• Storage diseases
• Muscle glycogenosis (phosphorylase kinase
  defficiency) etc.
• Mucopolysaccharidosis
• Mitochondrial diseases
• industrial agents--especially solvents
• heavy metals (lead, arsenic, mercury, etc.)
• Nutritional deficiencies White rice, dried fish

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• Thiamine deficiency

31
Thiamine

• "There is present in rice polishings a substance
  different from protein and salts, which is
  indispensable to health and the lack of which
  causes nutritional polyneuritis"                
                     
• Christian Eijkman and Gerrit Grijns, 1906

32
Thiamine

• Thiamine diphosphate (pyrophosphate), serves as a
  co-enzyme for several reactions that cleave C-C
  bonds, e.g., oxidative decarboxylation of
  alpha-keto acids (pyrovate Leucine, isoleucine,
  reactions in pentose monophosphate pathway.
  Many features of thiamine deficiency are result
  of inhibition of these enzymatic pathways or
  accumulation of their metabolites.
• Thiamine has specific role in neurons independent
  of metabolism.Thiamine its esters are present
  in axonal membranes electrical stimulation of
  nerves effect hydrolysis release of thiamine
  diphosphate and triphosphate.

33
Thiamine

• Vitamin is wide spread amongst a number of food
  sources esp. vegetables, outer layers of cereal
  grains (hence machine milled rice is a poor
  source), it is present in animal sources as
  phosphate esters. A substantial loss of vitamin
  takes place during cooking above 100C.
• Requirements increase in pregnancy, lactation,
  thyrotoxicosis and fever. Accelerated loss may
  occur with diuretic therapy, dialysis, diarrhea,
  malabsorption states, alcoholism, chronic
  malnutrition folate deficiency

34
BeriBeri

• Two major manifestations of Th. Def. involve
  cardiovascular system (wet beriberi) nervous
  system (dry beriberi). A typical patient has
  mixed symptoms involving both cardiovascular and
  nervous system, relative preponderance of these
  symptoms is related to duration and severity of
  deficiency.
• Severe physical exertion, high carbohydrate
  intake moderate chronic defficiency favor wet
  beriberi, whereas an equal deficiency with
  caloric restriction relative inactivity favors
  development of dry beriberi.

35
Cardiovascular manifestations

• Three major physiologic derangements are seen.
• Peripheral vasodilatation leading
  to a high output state.
• Retention of sodium and water
  leading to edema.
• Biventricular myocardial failure.

36
Cardiovascular manifestations

• Acute fulminant cardiovascular (Shoshin)
  beriberi, myocardial lesion is the central
  feature of a course in which dyspnea,
  restlessness, and anxiety eventuates into acute
  cardiovascular collapse death within hours to
  days. Physical findings include stocking-glove
  cyanosis, tachycardia, marked cardiomegaly,
  hepatomegaly, arterial bruits neck vein
  distention. Because of fulminant course edema may
  be minimal. Thiamine administration may restore
  BP but low output failure may supervene during
  treatment.

37
Neurologic Involvement

• Three forms of nervous system involvement occur.
  Peripheral neuropathy, Wernickes encephalopathy
  (cerebral beriberi) the Korsakoff syndrome.
• The neuropathy may or may not be painful
  characterized by a symmetric impairment of
  sensory, motor and reflex function that affects
  predominantly the distal parts of limbs.
  Histologic lesion is a non-inflammatory
  degeneration of myelin sheaths. There is no
  meaningful clinical distinction between this and
  alcoholic neuropathy.

38
Treatment

• Drug Category Vitamins -- Organic substances
  required by the body in small amounts for various
  metabolic processes. Vitamins may be synthesized
  in small or insufficient amounts in the body or
  not synthesized at all, thus requiring
  supplementation.
• Drug NameThiamine hydrochloride (Thiamilate) --
  Essential coenzyme that combines with ATP to form
  thiamine pyrophosphate. Dosage forms include a
  parenteral injection (l00 mg/mL) and tablets.

39
Sarsaparilla

• Sarsaparilla is the dried root of Smilax ornata,
  Hook. f. (N.O. Smilaceae), a climbing plant
  growing in Costa Rica.
• Action and Uses.Sarsaparilla is used in the
  treatment of chronic rheumatism, skin diseases,
  and in syphilis. It is extremely doubtful whether
  it exerts any action in these conditions, and its
  chief use is as a vehicle for the administration
  of mercury and potassium iodide.

40
Thiamine deficiency

• Macroscopic and microscopic considerations

41
External examination

• Mild malnutrition
• Anasarca
• Dilated neck large vessels
• Pupils have even diameter
• Normal antero-posterior thoracic diameter
• Protruding abdomen
• Atrophic lower extremity musculature

42
Internal examination

• Hydrothorax (bilateral, straw-colored transudate,
  300 ml)
• Hydropericardium (150 ml clear, transudate)
• Ascites (1000 ml, clear, straw-colored)
• Cardiomegaly, hepatosplenomegaly

43
Cardiovascular system

• Heart normal to severely enlarged
• Dilated right and left ventricles
• Globular shape (four-chamber dilation)
• Pale flabby myocardium
• Mural thrombi in atria

44
Cardiovascular system

• Patent coronary arteries
• No evidence of myocardial infarct
• No aortic and peripheral arteriosclerosis
• Microscopy mild myocardial hypertrophy
• Negative for necrosis or fibrosis
• No evidence of myocarditis and cardiomyopathy

45
Cardiomegaly and biventricular dilation
46
Heart - hypertrophy and ventricular dilation
47
Myocardium, HE stain
48
Respiratory system

• Tracheal and bronchial mucosa covered by frothy
  fluid
• Smooth and glistening pleural surface
• Heavy, dark-purple lung parenchyma
• Negative for consolidation
• Homogeneous dark purple cut surface
• Brownish fluid on pressure

49
Acute pulmonary congestion
50
Pulmonary edema
51
Pulmonary edema
52
Acute pulmonary edema, severe
53
Chronic passive pulmonary congestion
54
Gastrointestinal system/liver

• Petechial hemorrhage of gastric and bowel mucosa
• Hepatomegaly (2500 gr), dark brown and yellow
  cut surface, nutmeg pattern, no evidence of
  cirrhosis
• Microscopy central vein dilation, centrilobular
  hepatocytic atrophy, severe sinus congestion

55
Liver - congestion
56
Liver - centrilobular severe congestion
57
Liver - acute congestion
58
Spleen - splenomegaly
59
Central and peripheral nervous system

• Slightly thinned gyri and deep sulci
• Mamillary body, periventricular thalamus, fourth
  ventricular floor and anterior cerebellar
  petechial hemorrhage
• Lower extremity nerves hemorrhage, demyelination
  and axonal degeneration

60
Adult peripheral nerve - Toluidine blue stain
61
Peripheral nerve - demyelination
62
Peripheral neuron - axonal degeneration
63
Recent hemorrhage - mamillary body
64
Mamillary body - recent petechial hemorrhage
65
Syndromes of thiamine deficiency

• Polyneuropathy (dry beriberi)
• Cardiovascular syndrome (wet beriberi)
• Wernicke-Korsakoff syndrome

66
Polyneuropathy

• Symmetric, nonspecific peripheral neuropathy
• Demyelination
• Disruption of axons involving motor, sensory and
  reflex arcs (toe drop, foot drop, wrist drop)

67
Cardiovascular manifestation

• Peripheral vasodilation
• Rapid arteriovenous shunting of blood
• High output cardiac failure (severe congestion of
  internal organs)
• Peripheral edema (hydrothorax, hydropericardium,
  ascites)
• Heart may be normal or enlarged

68
Wernicke-Korsakoff syndrome

• Protracted severe deficiency
• Usually affects alcoholics in developed countries
• Symptoms ophthalmoplegia, nystagmus, ataxia of
  gait, mental function derangement
• Korsakoff psychosis retrograde amnesia,
  inability to acquire new information,
  confabulation

69
Involvement of nervous system

• Dilated capillaries
• Prominent endothelial cells
• Capillary leak - hemorrhage
• Infiltration by macrophages
• Cystic spaces with hemosiderin-laden macrophages

70
Thiamine metabolism

• Absorbed from the gut
• Phosphorylation follows absorption, thiamine
  pyrophosphate is formed which is a functionally
  active coenzyme form of vitamin B1

71
Functions of thiamine pyrophosphate

• Regulates oxidative carboxylation of alpha-keto
  acids, leading to the synthesis of adenosine
  triphosphate
• Acts as a cofactor for transketolase in a pentose
  phosphate pathway
• Maintains neural membranes and normal nerve
  conduction (little-understood manner)

72
Thiamine deficiency

• Underdeveloped countries scant diet is mostly
  composed of polished rice
• Developed countries chronic alcoholism
  (one-fourth of cases), pernicious vomiting of
  pregnancy or debilitating illnesses, protracted
  diarrhea
• Subclinical form may be manifested by refeeding
  or intravenous glucose therapy

73
An illness, known as Kakke (disease of legs), was
endemic to China at the turn of the century,
particularly at such ports as Kiang-Chow, Foo
Chow and Hong Kong. In 1897, 10,000 cases would
appear among Hong Kongs 250,000 inhabitants. It
was prevalent throughout East Asia, including the
Philippines, Malaysia and Indonesia. In Indonesia
it was called beri-beri (BB) beri refers to
weakness the duplication used to accentuate
meaning (very weak).
74
Its origins were debated for many years. The
Chinese felt BB was caused by a gaseous poison
that originated from the earth. Feet, in contact
with earth, were therefore first affected.
Pasteurs germ theory and the emergence of
microbiology as a discipline in the latter part
of the 19th century, led many to believe a
disease could only be caused by a positive agent
(e.g., infecting organism or toxin). While
theories varied a variety of organisms were held
responsible for BB. Studies did not support one
another each touted a new organism.
75
Diet was considered of lesser importance. Its
relevance slowly gained credence from several
parts of the world. Atjeh, Dutch East Indies,
1874. To combat BB, prevalent amongst the Dutch
East Indian fleet, native sailors had their
predominant rice diet modified to include
European food stuffs. A marked decline in
incidence followed. In 1875 several of the
fleets ships traveled to New Guinea.
76
During the voyage the crew reverted back to
native rations. Many of those who remained
behind maintained the European diet. Only those
who resumed their rice diet during the voyage or
those who refused to switch over to the varied
diet in Atjeh developed BB. Thereafter, a
European diet became compulsory ration for the
fleet and as Van Leent reported in 1880, BB had
disappeared from warships.
77
Tokyo, Japan, 1882. Kanehiro Takaki, a medical
officer in the Japanese Navy, emphasized the
importance of diet in preventing BB. His
hypothesis too little nitrogenous substances,
too much carbohydrate. He convinced a skeptical
Japanese admiralty to initiate dietary reforms.
Voyages would provide more fresh meat and
vegetables barley would occasionally be
substituted for rice. In 5 years BB was
eliminated from the Japanese Navy. Takaki would
later become an Admiral.
78
Java, Dutch East Indies, 1883. Christiaan Eijkman
(ik-man), a microbiologist, went to Java to find
the organism responsible for BB. He made an
accidental discovery.
79
Domestic fowl fed surplus cooked rice from the
wards of the military hospital developed a
BB-like neuritis. Early polyneuritis is shown
here.
80
Late polyneuritis in chickens is depicted here.
Eijkman termed this illness in chickens
polyneuritis gallinarum. When these chickens
were returned to their usual low-grade, uncooked
rice diet, they recovered. He was unable to
demonstrate chicken to chicken transmission and
could not induce the illness in chickens given
blood or body fluids taken from affected humans.
81
In contrast to unmilled rice which retained its
bran coat,
82
the rice used in the hospital kitchen was milled
and referred to as polished or white rice.
83
During milling, such as seen here, the polished
grains outer bran coating was removed.
84
Chickens became an animal model vital to the
study of BB, including the isolation and
identification of BB-preventing substance. A. G.
Voderman, a colleague of Eijkman, surveyed
several hundred thousand prisoners in 101 Java
and Madeira prisons in 1885 testing the bran coat
hypothesis. An astounding difference in the
incidence of BB was observed depending on whether
prisoners were served polished or unpolished
rice. Both Eijkman and Voderman, victims of
their microbiology training, searched for
responsible microorganisms.
85
In 1912, Casimir Funk would present results of
his epidemiologic and experimental studies that
would identify the importance of minute
quantities of substances found in food stuffs in
preserving normal metabolism and human nutrition.
He termed these substances vitamins. Absence of
a vitamin from the diet led to a new
conceptconsumption of a ration lacking a
definitive chemical substance could lead to a
disease of deficiency.
86
The clinical presentation of BB was related to
the degree and duration of the dietary deficit
milder cases were associated with polyneuritis
(dry BB) more severe cases included cardiac
involvement and serous effusions (wet BB). An
acute fulminant form included dyspnea,
palpitation and chest pain. Heavy muscular work
together with a chronic deficiency of moderate
severity and high carbohydrate intake, as likely
was the case in the Hong Kong crew, favors the
appearance of wet BB. A chronic deficiency with
caloric restriction and inactivity favors dry BB.
87
Manila, Philippines, 1909. Edward Vedders
studies had shown that rice polishings contained
a specific BB-preventing substance and which
therefore was lacking in white rice.
88
Robert Williams, a chemist, came to work with
Vedder and was given the task of further
characterizing and isolating the substance.
Williams returned to the States in 1915 and would
pursue his quest for many years. In 1927 the
vitamin was isolated in pure form by Jansen and
Donath and in crystalline form by Williams and
coworkers in 1933.
89
Soon after World War II, and the vicious fighting
between U.S. and Japanese armies at Bataan,
90
Juan Salcedo would demonstrate that BB could be
prevented
91
in this Peninsula of the Philippines, by
artificial enrichment of rice with this vitamin,
termed B1 or thiamine.