Sunshine and Cod Liver Oil: How Ancient Folklore Led to a Modern Diagnosis

1
Sunshine and Cod Liver Oil How Ancient Folklore
Led to a Modern Diagnosis

• Elisabeth Goldwater, MD
• Texas Tech Health Sciences Center
• Department of Pediatrics
• Lubbock, Texas

2
Abstract

• Rickets is a disease of Vitamin D
  deficiency that plagued children for centuries
  yet perplexed all who investigated its cause. In
  the early 20th century, rickets was widespread
  among children living in the northern cities of
  the United States and Europe. It had been
  observed that the addition of cod liver oil to
  the diet had the ability to heal this mysterious
  ailment. At the same time, scientists noted the
  curative effects of sunshine on these bony
  deformities. The fact that both diet and
  environment played a role in this disease was
  puzzling. Advances in research led to the
  discovery of Vitamin D, the elusive factor
  present in cod liver oil that was responsible for
  these therapeutic benefits. Further studies in
  the early 1920s determined that sunlight
  mediated the cutaneous synthesis of Vitamin D.
  The connection between the dietary and
  photosynthesized sources of Vitamin D provided
  the knowledge to eradicate rickets. The public
  health initiatives to prevent rickets have been
  extremely successful, yet children today continue
  to be afflicted with this disease. A modern
  awareness of this disorder is crucial. This case
  presentation illustrates how a seemingly historic
  disease can still have a contemporary emphasis.

3
Background/Objectives

• Looking retrospectively at rickets illustrates
  the great historical advances that have been made
  in preventing and curing this disease.
• This case illustrates the classic clinical
  findings of rickets.
• It highlights the fact that general pediatricians
  may be confronted by this disease and serves as a
  reminder to be vigilant in current medical
  practices.
• It points out the vulnerability of certain
  populations to rickets, particularly in infants
  that are exclusively breastfed, African American
  infants, and infants residing in northern
  latitudes.
• It provides overwhelming evidence of the
  importance of public health campaigns in the
  prevention and eradication of disease.

4
Case Presentation
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History of Present Illness

• Chief Complaint
• falls down a lot
• History of Present Illness
• 23 month-old African American female with a six
  month history of difficulty walking
• Initially started walking more slowly, now
  stumbles frequently and is unable to fully extend
  legs
• Mom also noticed swelling of the patients
  wrists, knees, and ankles over the past 4 months
• Occasionally points to knees/wrists and says they
  hurt

6
Review of Systems

• General afebrile, no weight loss, normal
  activity level, no fatigue stumbling frequently
• Skin no rashes or lesions
• HEENT no concerns about vision or hearing
  nasal congestion/rhinorrhea itchy watery eyes
• Respiratory no cough, no increased work of
  breathing
• CV no history of heart murmur
• GI normal appetite no vomiting no diarrhea
• Musculoskeletal as per HPI
• Neuro no weakness no motor/sensory deficits

7
Past Medical History

• Birth Hx Term C-Section BW 610oz normal
  newborn nursery course no complications
• Past Hx Allergic rhinitis no previous ER visits
  or hospitalizations
• Past Surgical Hx born with supernumerary digit
  on left hand which was surgically removed at 10
  months of age

8
Social History

• Lives in West Texas with mother and grandmother
• No siblings
• Mother is a 3rd year law student, employed by a
  local law firm Grandmother is retired and serves
  as the daytime caretaker
• No pets
• No one in the household uses tobacco products
• No daycare

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Diet History

• Breastfed until 18 months of age
• Whole milk introduced at 15 months of age (one 4
  oz serving/day) along with one serving of juice
  per day and several servings of water
• Rice cereal introduced at 6 months of age
• Baby foods introduced at 7 months of age
• Currently eats table foods- meat, vegetables, and
  fruit
• Picky eater according to mom

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More History

• Medications Zyrtec
• Allergies NKDA
• Family Hx Grandmother with HTN otherwise
  negative
• Development
• Sit alone without support 6 months
• Pull self to standing position 9 months
• Walking 12 months
• Language and fine motor development were WNL
• For the past few months she has had increasing
  difficulty running climbing stairs

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Physical Exam

• General slightly fussy but cooperative female
  infant
• Vitals T 98.4 P120 R28
  BP 98/70
• Weight 10.4 kg (10) Length 80 cm (5-10)
• HEENT frontal bossing noted, EOMI, PERRL, TMs
  clear B Oropharynx moist normal-appearing
  dentition
• Neck supple, no lymphadenopathy
• CV RRR no murmur
• Lungs CTA B good air movement throughout
• Chest firm, palpable rounded prominences at the
  end of each rib that are apparent on visual
  inspection of the thorax

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Physical Exam

• Abdomen soft, nondistended, normal active bowel
  sounds no masses, no hepatosplenomegaly
• GU Tanner Stage 1 female normal external female
  genitalia
• Neuro DTRs 2, motor and sensory intact Gait
  walked slowly with knees slightly flexed
• Ext enlarged wrists, knees, and ankles by
  inspection and palpation. 1-2 inch section of
  widening across the wrist joint. Slightly
  decreased range of motion in wrists, knees, and
  ankles. Unable to fully extend legs from the
  knees. No pain noted with passive or active
  motion. No joint warmth, erythema, or tenderness
  noted with palpation. Slightly bowing of the legs
  when standing.
• Skin no rashes or lesions present

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Rachitic Rosary
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Enlargement of Wrists
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(No Transcript)
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Differential Diagnosis- Rickets

• Inadequate Synthesis/Dietary Deficiency of
  Vitamin D
• Inadequate exposure to sunlight/Dark skin
  pigmentation
• Limited dietary intake of fortified foods
• Poor maternal nutrition
• Decreased absorption of Fat-Soluble Vitamin D
• Cholestatic liver disease
• Pancreatic insufficiency
• Biliary tract obstruction
• Celiac sprue
• Extensive small bowel disease

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Differential Diagnosis- Rickets

• Problems with Vitamin D Metabolism
• Increased degradation of Vitamin D and 25 (OH) D
  (exmeds)
• Phenytoin
• Phenobarbital
• Rifampin
• Impaired synthesis of 25 (OH) D
• Diffuse Liver Disease
• Decreased synthesis of 1,25 (OH)2 D
• Advanced Renal Disease
• Vitamin D dependent rickets Type 1
  (deficiency of renal
  a1-hydroxylase)

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Differential Diagnosis-Rickets

• End-Organ resistance to 1,25 (OH)2 D
• Vitamin D Dependent Rickets Type 2
  (inherited absence/defective receptors)
• Phosphate Depletion
• Chronic antacid use (aluminum hydroxide binds
  phosphate leading to poor absorption)
• X-linked hypophosphatemic rickets/ Familial
  Hypophosphatemia/ Vitamin D resistant rickets
  (excess renal tubule excretion of phosphate)

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Diagnosis- Rickets

• This patient had several risk factors for
  developing a Vitamin D deficiency from inadequate
  intake/synthesis.
• Dietary Breastfed until 18 months of age.
  Vitamin D-fortified milk (only 120 ml/day) was
  not introduced until 15 months.
• Breastmilk contains a Vitamin D concentration of
  25 IU/L.
• The recommended adequate intake of vitamin D is
  200 IU/day.
• Therefore the patient was not getting the
  recommended amount of Vitamin D for normal bone
  metabolism.
• Darker skin pigmentation limited the cutaneous
  synthesis of Vitamin D in this patient.
• Mom reports that the patient received very little
  sun exposure and spent most of her time indoors.

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Laboratory Investigation

• Laboratory Workup

• Typical Lab findings in Vitamin D deficiency
• Calcium can be normal or low
• Phosphorus is usually low but can be normal (as
  in this patient who was receiving a limited
  amount of Vitamin D)
• PTH is increased
• 25 (OH) D is low
• 1-25 (OH)2 D can be low, normal, or high (This
  wide variation is due to upregulation of renal 1
  a-hydroxylase due to hypophosphatemia and
  hyperparathyroidism)
• Alkaline Phosphatase will be high

88
Calcium 9.7 (normal) Phosphorus 3.5
(normal) Alkaline Phosphatase 1118 (high) 1-25
(OH)2 D 95 (normal)
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Radiographic Findings
-Fraying of the metaphysis -loss of the
normally sharp border -Cupping of the
metaphysis- edge becomes concave rather than flat
or convex -Widening of the distal end of the
metaphysis -Thickening of the growth plate
secondary to decreased calcification -Line of
healing evident at metaphysis secondary to the
introduction of 4 oz whole milk/day at 15 months
(a small source of Vitamin D)
This patients X-rays at time of diagnosis
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Radiographic Findings One Year after Diagnosis
and Treatment

• The patient was started on daily high dose
  Vitamin D therapy for 4 weeks
• This was followed by daily Vitamin D
  supplementation of 200 IU
• Dietary adjustments were made to provide more
  Vitamin D-rich foods
• These changes resulted in dramatic improvements
• At a follow-up appointment one year later, the
  bony deformities were healed and the patient
  showed no clinical signs of rickets

This patients X-ray 1 year after diagnosis and
treatment
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Clinical features of Rickets

• Rickets is a disease of growing bone due to
  unmineralized matrix at the growth plates
• Vitamin D mediates calcium absorption and is a
  crucial factor in the progression of bone
  mineralization
• Some of the clinical features present in rickets
  include
• Rachitic rosary widening of the costochondral
  junctions
• Enlargement of wrists/ankles widening of the
  growth plates
• Craniotabes softening of the cranial bones
• Harrison groove horizontal depression along the
  lower anterior chest due to pulling of the ribs
  by the diaphragm during inspiration
• Valgus or varus deformities/Anterior bowing of
  the tibia and femur softening of the bones

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Rickets Throughout History

• Recorded in medical writings as early as the
  1st-2nd century AD
• Soranus, a Roman physician of the time, noted
  bony deformities were more common among infants
  in Rome than in Greece
• Rickets was endemic in England in the mid-17th
  century
• Turn of the 20th century, it was rampant among
  poor children living in the northern cities of
  the United States and Europe
• 1909 among infants lt18 mo who had died, Schmorl
  et al found that 96 had histopathological
  evidence of rickets at autopsy

25
Rickets Throughout History

• Francis Glisson, a Cambridge physician,
  published this statement regarding rickets in
  1650
• We affirm therefore, that this disease doth
  rarely invade children presently at birth, or
  before they are 6 months old (yea perhaps before
  the ninth month) but after that time it beginneth
  little and little daily to rage more and more to
  the period of eighteen months

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Suggested Cures for Rickets

• As found in Glissons De Rachitide
• Cautery
• Incisions to draw out bad humors
• Blistering
• Ligature of soft wool around the limb to retard
  the return of blood
• Splinting and artificial suspension of infant

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The Value of Cod Liver Oil

• 1861- Trousseau of France ventured that cod liver
  oil could cure rickets.
• 1889- Bland Sutton observed rickets among lion
  cubs at the London Zoo. Addition of cod liver oil
  to their diets helped the cubs recover
  completely.
• 1918- Sir Edward Mellanby cured rickets in dogs
  by feeding them cod liver oil. He suggested that
  there was an anti-rachitic factor present in
  cod liver oil that was either Vitamin A or a
  substance similar to it.
• Cod liver oil was recommended for rickets, yet
  its scientific basis was not understood.

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The Value of Sunshine

• 1890- Palm noted that despite a better diet,
  infants living in Britain were more at risk for
  rickets than infants living in the tropics.
• After studying the geographical distribution of
  rickets, he concluded that rickets was caused by
  a lack of exposure to sunlight.
• As a result of his research, he recommended
  systematic use of sun-baths as a preventative
  and therapeutic measure in rickets.

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Advances in Nutritional Biochemistry

• 1920- researchers discover that irradiating
  certain foods destroyed fat-soluble Vitamin A.
• 1922- Edward McCollum irradiated cod liver oil
  but noted that it still retained a substance that
  was protective against rickets.
• He concluded that this substance was distinct
  from fat-soluble Vitamin A, and the purpose of
  this substance involved the metabolism of bones.
• This newly discovered substance was the fourth
  vitamin discovered, therefore it was called
  Vitamin D
• 1931- Askew determined the chemical makeup of
  Vitamin D found in food.
• Continuing research further delineated the
  properties of Vitamin D and its importance in
  diet and bone metabolism.

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Making the Vitamin D Connection

• 1919- K. Huldschinsky conducted a study where he
  cured children with rickets by using ultraviolet
  light
• 1919-1922- Dr. Harriette Chick studied the
  treatment of rickets in Vienna and demonstrated
  by radiographic evidence that bone healing was
  equally achieved by ultraviolet light or cod
  liver oil.
• 1936- Windaus determines the chemical structure
  of Vitamin D synthesized in the skin via
  sunlight.
• This body of research allowed scientists to
  determine the relationship between the Vitamin D
  found in foods and the one produced in the skin
  and their collective role in bone metabolism and
  rickets.

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Vitamin D deficiency

• Vitamin D deficiency remains the most common
  cause of rickets worldwide.
• Breast milk is a poor source of Vitamin D
• Infants that are exclusively breast-fed rely on
  cutaneous synthesis of Vitamin D
• Cutaneous synthesis is affected by increased skin
  pigmentation, as well as the ineffectiveness of
  the winter sun in promoting Vitamin D synthesis.

32
Infants at highest risk for Rickets

• African American infants that are exclusively
  breastfed
• Infants living in northern industrialized cities
• Infants where cultural practices include covering
  of the majority of skin or limited sun exposure
• Infants whose mothers are deficient in Vitamin D,
  thus lessening the amount of transplacental
  Vitamin D or reducing the content of Vitamin D in
  breastmilk
• Infants who have unconventional dietary
  practices, such as vegan diets or unfortified
  milk

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Public Health Initiatives

• Few foods are naturally rich in Vitamin D
• Dietary sources with high Vitamin D content
  include fish liver oils, fatty fish, egg yolks
• 1930s Awareness brought about the fortification
  of milk with Vitamin D
• Baby formulas are also fortified with Vitamin D
• Experts began promoting sensible sunbathing
  for emphasis on Vitamin D

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Treatment for Nutritional Rickets

• Treatment
• Daily, high dose Vitamin D ranging from
  2,000-5,000 IU/day over 4-6 weeks
• Alternative 300,000-600,000 IU of Vitamin D
  administered orally/intramuscularly as 2-4 doses
  over 1 day
• This should be followed by daily Vitamin D
  supplementation of 200 IU/day (given as
  multivitamin)
• Confirm that the child is getting adequate
  calcium/ phosphorus in their diet

35
Prevention of Nutritional Rickets

• The following groups should receive 200 IU
  Vitamin D supplementation per day
• All breastfed infants (unless they consume at
  least 500 ml per day of vitamin D-fortified
  formula or milk). Supplementation should begin in
  the first 2 months of life.
• All nonbreastfed infants who take less than 500
  ml per day of vitamin D-fortified formula or
  milk.
• Children/Adolescents who do not have regular
  sunlight exposure or do not take at least 500 ml
  per day of vitamin D-fortified milk.

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Conclusions

• Nutritional rickets is a very real disease that
  still exists in an era of greater knowledge and
  understanding about its source.
• Scientists historically faced many challenges in
  determining the etiology of this mysterious
  disease.
• As pediatricians, we should be aware of
  populations susceptible to vitamin D deficiency
  and continue these historic efforts to prevent
  rickets.

French advertisement promoting Cod Liver Oil
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References

• Kliegman R, Behrman R, Jenson H. Nelson Textbook
  of Pediatrics 18th Edition. Philadelphia
  Elsevier Science, 2007. Pages 253-262
• Gartner L, Greer F. Prevention of Rickets and
  Vitamin D Deficiency New Guidelines for Vitamin
  D Intake. Pediatrics 2003 111(4) 908-910
• Rajakumar K. Vitamin D, Cod-Liver Oil, Sunlight,
  and Rickets A Historical Perspective. Pediatrics
  2003 112 e132-e135
• Thomas S, Rajakumar K. Reemerging Nutritional
  Rickets. Archives of Pediatrics and Adolescent
  Medicine 2005 159 335-341
• Nield L, Mahajan P, Joshi A, Kamat D. Rickets
  Not a Disease of the Past. American Family
  Physician 2006 74(4) 619-626
• Dawodu A, Wagner C. Mother-child vitamin D
  deficiency an international perspective.
  Archives of Diseases in Childhood 2007 92
  737-740